{"id":23688,"date":"2024-09-04T10:03:31","date_gmt":"2024-09-04T07:03:31","guid":{"rendered":"https:\/\/xenobg.com\/?p=23688"},"modified":"2024-09-04T10:07:24","modified_gmt":"2024-09-04T07:07:24","slug":"sodata-za-hlyab-mozhe-da-lekuva-rak-metformin-mozhe-da-go-predizvika","status":"publish","type":"post","link":"https:\/\/xenobg.com\/en\/sodata-za-hlyab-mozhe-da-lekuva-rak-metformin-mozhe-da-go-predizvika\/","title":{"rendered":"\u0421\u043e\u0434\u0430\u0442\u0430 \u0437\u0430 \u0445\u043b\u044f\u0431 \u043c\u043e\u0436\u0435 \u0434\u0430 \u043b\u0435\u043a\u0443\u0432\u0430 \u0440\u0430\u043a. \u041c\u0435\u0442\u0444\u043e\u0440\u043c\u0438\u043d \u043c\u043e\u0436\u0435 \u0434\u0430 \u0433\u043e \u043f\u0440\u0435\u0434\u0438\u0437\u0432\u0438\u043a\u0430"},"content":{"rendered":"\n<p>\u041a\u0430\u043a\u0442\u043e \u043c\u043d\u043e\u0437\u0438\u043d\u0430 \u0447\u0438\u0442\u0430\u0442\u0435\u043b\u0438 \u0437\u043d\u0430\u044f\u0442, \u0438\u0437\u043f\u043e\u043b\u0437\u0432\u0430\u043d\u0435\u0442\u043e \u043d\u0430 \u0441\u043e\u0434\u0430 \u0431\u0438\u043a\u0430\u0440\u0431\u043e\u043d\u0430\u0442 \u0437\u0430 \u043b\u0435\u0447\u0435\u043d\u0438\u0435 \u043d\u0430 \u0440\u0430\u043a &nbsp;\u0431\u0435\u0448\u0435 \u043e\u0431\u044f\u0432\u0435\u043d\u043e \u0437\u0430 &#8222;\u0448\u0430\u0440\u043b\u0430\u0442\u0430\u043d\u0441\u043a\u0430 \u043c\u0435\u0434\u0438\u0446\u0438\u043d\u0430&#8220; \u043e\u0442 \u043c\u043d\u043e\u0433\u043e \u0433\u043e\u0432\u043e\u0440\u0438\u0442\u0435\u043b\u0438 \u043d\u0430 \u043e\u0444\u0438\u0446\u0438\u0430\u043b\u043d\u0430\u0442\u0430 \u043c\u0435\u0434\u0438\u0446\u0438\u043d\u0430, \u043a\u0430\u043a\u0442\u043e \u0438 \u043e\u0442 \u043d\u044f\u043a\u043e\u043b\u043a\u043e &#8222;\u043d\u0430\u0431\u043b\u044e\u0434\u0430\u0432\u0430\u0449\u0438&#8220; \u0433\u0440\u0443\u043f\u0438. \u0415\u0442\u043e \u043d\u044f\u043a\u043e\u0438 \u043b\u0438\u043d\u043a\u043e\u0432\u0435 \u0441 \u0438\u043d\u0444\u043e\u0440\u043c\u0430\u0446\u0438\u044f, \u043a\u043e\u044f\u0442\u043e \u0442\u043e\u0442\u0430\u043b\u043d\u043e \u043e\u0442\u0440\u0438\u0447\u0430 \u0443\u043f\u043e\u0442\u0440\u0435\u0431\u0430\u0442\u0430 \u043d\u0430 \u0441\u043e\u0434\u0430 \u0431\u0438\u043a\u0430\u0440\u0431\u043e\u043d\u0430\u0442 \u043f\u0440\u0438 \u0440\u0430\u043a.<\/p>\n\n\n\n<figure class=\"wp-block-embed is-type-wp-embed is-provider-science-based-medicine wp-block-embed-science-based-medicine\"><div class=\"wp-block-embed__wrapper\">\n<blockquote class=\"wp-embedded-content\" data-secret=\"ygEaAIPPuS\"><a href=\"https:\/\/sciencebasedmedicine.org\/another-cancer-tragedy-in-the-making\/\">Another cancer tragedy in the making<\/a><\/blockquote><iframe loading=\"lazy\" class=\"wp-embedded-content\" sandbox=\"allow-scripts\" security=\"restricted\" style=\"position: absolute; visibility: hidden;\" title=\"&#8220;Another cancer tragedy in the making&#8221; &#8212; Science-Based Medicine\" src=\"https:\/\/sciencebasedmedicine.org\/another-cancer-tragedy-in-the-making\/embed\/#?secret=z7z9Dwg4WX#?secret=ygEaAIPPuS\" data-secret=\"ygEaAIPPuS\" width=\"600\" height=\"338\" frameborder=\"0\" marginwidth=\"0\" marginheight=\"0\" scrolling=\"no\"><\/iframe>\n<\/div><\/figure>\n\n\n\n<p><a href=\"https:\/\/scienceblog.cancerresearchuk.org\/2014\/03\/24\/dont-believe-the-hype-10-persistent-cancer-myths-debunked\/#fungus\">https:\/\/scienceblog.cancerresearchuk.org\/2014\/03\/24\/dont-believe-the-hype-10-persistent-cancer-myths-debunked\/#fungus<\/a><\/p>\n\n\n\n<figure class=\"wp-block-embed is-type-wp-embed is-provider-edzard-ernst wp-block-embed-edzard-ernst\"><div class=\"wp-block-embed__wrapper\">\n<blockquote class=\"wp-embedded-content\" data-secret=\"amGEP5dG3f\"><a href=\"https:\/\/edzardernst.com\/2017\/02\/this-must-be-the-most-sickening-cancer-scam-i-have-seen-for-a-while\/\">This must be the most sickening cancer scam I have seen for a while<\/a><\/blockquote><iframe loading=\"lazy\" class=\"wp-embedded-content\" sandbox=\"allow-scripts\" security=\"restricted\" style=\"position: absolute; visibility: hidden;\" title=\"&#8220;This must be the most sickening cancer scam I have seen for a while&#8221; &#8212; Edzard Ernst\" src=\"https:\/\/edzardernst.com\/2017\/02\/this-must-be-the-most-sickening-cancer-scam-i-have-seen-for-a-while\/embed\/#?secret=lnvhK8q0Mk#?secret=amGEP5dG3f\" data-secret=\"amGEP5dG3f\" width=\"600\" height=\"338\" frameborder=\"0\" marginwidth=\"0\" marginheight=\"0\" scrolling=\"no\"><\/iframe>\n<\/div><\/figure>\n\n\n\n<p>\u041d\u044f\u043a\u043e\u0438 \u043e\u0442 \u0442\u0432\u044a\u0440\u0434\u0435\u043d\u0438\u044f\u0442\u0430 \u043d\u0430 \u043f\u0440\u0438\u0432\u044a\u0440\u0436\u0435\u043d\u0438\u0446\u0438\u0442\u0435 \u043d\u0430 \u0441\u043e\u0434\u0430\u0442\u0430 \u0437\u0430 \u0445\u043b\u044f\u0431 \u043d\u0435 \u0441\u0430 \u0441\u044a\u0432\u0441\u0435\u043c \u0442\u043e\u0447\u043d\u0438 (\u043d\u0430\u043f\u0440. \u043c\u0435\u0445\u0430\u043d\u0438\u0437\u043c\u0430 \u043d\u0430 \u0434\u0435\u0439\u0441\u0442\u0432\u0438\u0435). \u041f\u043e-\u0441\u043f\u0435\u0446\u0438\u0430\u043b\u043d\u043e, \u043f\u0440\u0438\u0432\u044a\u0440\u0436\u0435\u043d\u0438\u0446\u0438\u0442\u0435 \u043d\u0430 \u0441\u043e\u0434\u0430\u0442\u0430 \u0437\u0430 \u0445\u043b\u044f\u0431 \u0442\u0432\u044a\u0440\u0434\u044f\u0442, \u0447\u0435 \u0440\u0430\u043a\u043e\u0432\u0430\u0442\u0430 \u0442\u044a\u043a\u0430\u043d \u0435 \u0441\u0438\u043b\u043d\u043e \u043a\u0438\u0441\u0435\u043b\u0438\u043d\u043d\u0430 \u0438 \u0447\u0435 \u0442\u0430\u0437\u0438 \u043a\u0438\u0441\u0435\u043b\u0438\u043d\u043d\u0430 \u0441\u0440\u0435\u0434\u0430 \u043f\u043e\u0434\u0445\u0440\u0430\u043d\u0432\u0430 \u0433\u044a\u0431\u0438\u0447\u043a\u0438\u0442\u0435, \u043f\u0440\u0438\u0447\u0438\u043d\u044f\u0432\u0430\u0449\u0438 \u0440\u0430\u043a. \u0418\u0441\u0442\u043e\u0440\u0438\u044f\u0442\u0430 \u0440\u0430\u0437\u043a\u0430\u0437\u0432\u0430, \u0447\u0435 \u043f\u0440\u0438\u043b\u0430\u0433\u0430\u043d\u0435\u0442\u043e \u043d\u0430 \u0441\u043e\u0434\u0430 \u0437\u0430 \u0445\u043b\u044f\u0431 \u0430\u043b\u043a\u0430\u043b\u0438\u0437\u0438\u0440\u0430 \u0442\u044a\u043a\u0430\u043d\u0438\u0442\u0435 \u0438 \u0442\u043e\u0432\u0430 \u0443\u0431\u0438\u0432\u0430 \u0433\u044a\u0431\u0438\u0447\u043a\u0438\u0442\u0435, \u0442\u044a\u0439 \u043a\u0430\u0442\u043e \u0442\u0435 \u0441\u0435 \u043d\u0443\u0436\u0434\u0430\u044f\u0442 \u043e\u0442 \u043a\u0438\u0441\u0435\u043b\u0430 \u0441\u0440\u0435\u0434\u0430, \u0437\u0430 \u0434\u0430 \u0440\u0430\u0441\u0442\u0430\u0442. \u041a\u043e\u043b\u043a\u043e\u0442\u043e \u0438 \u0434\u0430 \u0435 \u0441\u0442\u0440\u0430\u043d\u043d\u043e, \u043a\u0440\u0438\u0442\u0438\u043a\u0438\u0442\u0435 \u043d\u0430 &#8222;\u0440\u0430\u0437\u043e\u0431\u043b\u0438\u0447\u0438\u0442\u0435\u043b\u0438\u0442\u0435&#8220; 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\u043f\u043e\u0434\u043a\u0438\u0441\u0435\u043b\u044f\u0432\u0430\u043d\u0435 \u043d\u0430 \u0432\u044a\u0442\u0440\u0435\u0448\u043d\u043e\u0441\u0442\u0442\u0430 \u043d\u0430 \u0442\u0443\u043c\u043e\u0440\u0430 (\u0447\u0440\u0435\u0437 \u043f\u043e\u0432\u0438\u0448\u0430\u0432\u0430\u043d\u0435 \u043d\u0430 \u043d\u0438\u0432\u0430\u0442\u0430 \u043d\u0430 CO2) \u0438 \u0430\u043b\u043a\u0430\u043b\u0438\u0437\u0438\u0440\u0430\u043d\u0435 \u043d\u0430 \u0432\u044a\u043d\u0448\u043d\u0430\u0442\u0430 \u0447\u0430\u0441\u0442 (\u0447\u0440\u0435\u0437 \u043d\u0435\u0443\u0442\u0440\u0430\u043b\u0438\u0437\u0438\u0440\u0430\u043d\u0435 \u043d\u0430 \u043c\u043b\u0435\u0447\u043d\u0430\u0442\u0430 \u043a\u0438\u0441\u0435\u043b\u0438\u043d\u0430). \u0422\u0440\u0435\u0442\u043e, \u0442\u043e\u0439 \u043f\u043e\u043a\u0430\u0437\u0432\u0430, \u0447\u0435 \u043f\u0440\u0438\u043b\u0430\u0433\u0430\u043d\u0435\u0442\u043e \u043d\u0430 \u043c\u0435\u0442\u0444\u043e\u0440\u043c\u0438\u043d \u0438\u043c\u0430 \u0441\u0442\u0438\u043c\u0443\u043b\u0438\u0440\u0430\u0449 \u0440\u0430\u043a\u0430 \u0435\u0444\u0435\u043a\u0442 \u043f\u043e\u0440\u0430\u0434\u0438 \u0441\u043f\u043e\u0441\u043e\u0431\u043d\u043e\u0441\u0442\u0442\u0430 \u043d\u0430 \u0442\u043e\u0432\u0430 \u043b\u0435\u043a\u0430\u0440\u0441\u0442\u0432\u043e \u0434\u0430 \u0443\u0432\u0435\u043b\u0438\u0447\u0430\u0432\u0430 \u0441\u0438\u043d\u0442\u0435\u0437\u0430 \u043d\u0430 \u043c\u043b\u0435\u0447\u043d\u0430 \u043a\u0438\u0441\u0435\u043b\u0438\u043d\u0430 \u0432\u044a\u0432 \u0432\u0441\u044f\u043a\u0430 \u043a\u043b\u0435\u0442\u043a\u0430.<\/p>\n\n\n\n<p>\u0418 \u0442\u0430\u043a\u0430, \u0430\u043a\u043e \u0441\u043e\u0434\u0430\u0442\u0430 \u0437\u0430 \u0445\u043b\u044f\u0431 \u0435 \u0442\u0435\u0440\u0430\u043f\u0435\u0432\u0442\u0438\u0447\u043d\u0430 \u0437\u0430 \u0440\u0430\u043a, \u0442\u043e\u0433\u0430\u0432\u0430 \u043a\u0430\u043a\u044a\u0432 \u0435 \u043f\u0440\u043e\u0442\u043e\u043a\u043e\u043b\u044a\u0442. \u0412 \u043f\u0440\u043e\u0443\u0447\u0432\u0430\u043d\u0435\u0442\u043e \u0435 \u0438\u0437\u043f\u043e\u043b\u0437\u0432\u0430\u043d\u043e \u043f\u0435\u0440\u043e\u0440\u0430\u043b\u043d\u043e \u043f\u0440\u0438\u043b\u043e\u0436\u0435\u043d\u0438\u0435 \u043d\u0430 \u0447\u043e\u0432\u0435\u0448\u043a\u0430 \u0435\u043a\u0432\u0438\u0432\u0430\u043b\u0435\u043d\u0442\u043d\u0430 \u0434\u043e\u0437\u0430 (\u0427\u0415\u0414) \u043e\u0442 \u043e\u043a\u043e\u043b\u043e 250 mg\/kg \u0434\u043d\u0435\u0432\u043d\u043e \u0437\u0430 \u043f\u0435\u0440\u0438\u043e\u0434 \u043e\u0442 8 \u0441\u0435\u0434\u043c\u0438\u0446\u0438. \u0422\u043e\u0432\u0430 \u043e\u0437\u043d\u0430\u0447\u0430\u0432\u0430, \u0447\u0435 \u043f\u0435\u0440\u043e\u0440\u0430\u043b\u043d\u0430 \u0434\u043e\u0437\u0430 \u043e\u0442 \u043e\u043a\u043e\u043b\u043e 20 \u0433 \u0434\u043d\u0435\u0432\u043d\u043e \u0431\u0438 \u0442\u0440\u044f\u0431\u0432\u0430\u043b\u043e \u0434\u0430 \u0435 \u0434\u043e\u0441\u0442\u0430\u0442\u044a\u0447\u043d\u0430 \u0437\u0430 \u043f\u043e\u0432\u0435\u0447\u0435\u0442\u043e \u0445\u043e\u0440\u0430. \u041f\u0440\u0438\u0447\u0438\u043d\u0430\u0442\u0430, \u043f\u043e\u0440\u0430\u0434\u0438 \u043a\u043e\u044f\u0442\u043e \u0441\u043f\u043e\u043c\u0435\u043d\u0430\u0432\u0430\u043c \u0434\u043e\u0437\u0430\u0442\u0430 \u043e\u0442 20 \u0433, \u0435, \u0447\u0435 \u0442\u044f \u0441\u0435 \u043e\u043a\u0430\u0437\u0432\u0430 \u0438 \u043d\u0430\u0439-\u0448\u0438\u0440\u043e\u043a\u043e \u0438\u0437\u043f\u043e\u043b\u0437\u0432\u0430\u043d\u0438\u044f\u0442 \u0440\u0435\u0436\u0438\u043c \u043d\u0430 \u0434\u043e\u0437\u0438\u0440\u0430\u043d\u0435 \u0437\u0430 \u043f\u043e\u0432\u0438\u0448\u0430\u0432\u0430\u043d\u0435 \u043d\u0430 \u0435\u0444\u0435\u043a\u0442\u0438\u0432\u043d\u043e\u0441\u0442\u0442\u0430 \u0441\u0440\u0435\u0434 \u0441\u043f\u043e\u0440\u0442\u0438\u0441\u0442\u0438\u0442\u0435. \u0415\u0444\u0435\u043a\u0442\u044a\u0442 \u043d\u0430 \u043f\u043e\u0432\u0438\u0448\u0430\u0432\u0430\u043d\u0435 \u043d\u0430 \u0440\u0430\u0431\u043e\u0442\u043e\u0441\u043f\u043e\u0441\u043e\u0431\u043d\u043e\u0441\u0442\u0442\u0430 \u0441\u0435 \u043f\u043e\u0441\u0442\u0438\u0433\u0430 \u0447\u0440\u0435\u0437 \u0441\u044a\u0449\u0438\u044f \u043c\u0435\u0445\u0430\u043d\u0438\u0437\u044a\u043c, \u0441 \u043a\u043e\u0439\u0442\u043e \u0441\u043e\u0434\u0430\u0442\u0430 \u0437\u0430 \u0445\u043b\u044f\u0431 \u0435 \u0442\u0435\u0440\u0430\u043f\u0435\u0432\u0442\u0438\u0447\u043d\u0430 \u0437\u0430 \u0440\u0430\u043a\u0430 &#8211; \u0442.\u0435. \u043d\u0435\u0443\u0442\u0440\u0430\u043b\u0438\u0437\u0438\u0440\u0430\u043d\u0435 \u043d\u0430 \u043c\u043b\u0435\u0447\u043d\u0430\u0442\u0430 \u043a\u0438\u0441\u0435\u043b\u0438\u043d\u0430 (\u043c\u043b\u0435\u0447\u043d\u0430\u0442\u0430 \u043a\u0438\u0441\u0435\u043b\u0438\u043d\u0430 \u043d\u0430\u0441\u044a\u0440\u0447\u0430\u0432\u0430 \u043c\u0443\u0441\u043a\u0443\u043b\u043d\u0430\u0442\u0430 \u0443\u043c\u043e\u0440\u0430) \u0438 \u0443\u0432\u0435\u043b\u0438\u0447\u0430\u0432\u0430\u043d\u0435 \u043d\u0430 CO2 (\u043a\u043e\u0435\u0442\u043e \u043f\u043e\u0434\u043e\u0431\u0440\u044f\u0432\u0430 \u043e\u043a\u0441\u0438\u0433\u0435\u043d\u0430\u0446\u0438\u044f\u0442\u0430 \u043d\u0430 \u0442\u044a\u043a\u0430\u043d\u0438\u0442\u0435 \u0438 \u0434\u043e\u043f\u044a\u043b\u043d\u0438\u0442\u0435\u043b\u043d\u043e \u043f\u043e\u0442\u0438\u0441\u043a\u0430 \u0441\u0438\u043d\u0442\u0435\u0437\u0430 \u043d\u0430 \u043c\u043b\u0435\u0447\u043d\u0430 \u043a\u0438\u0441\u0435\u043b\u0438\u043d\u0430).<\/p>\n\n\n\n<p>\u0415\u0442\u043e \u0432\u0438 \u0433\u043e, \u043f\u0440\u0438\u044f\u0442\u0435\u043b\u0438. \u0421\u043b\u0435\u0434 \u0434\u0435\u0441\u0435\u0442\u0438\u043b\u0435\u0442\u0438\u044f \u043d\u0430 \u0430\u0431\u0441\u043e\u043b\u044e\u0442\u043d\u0430 \u043d\u0435\u043a\u043e\u043c\u043f\u0435\u0442\u0435\u043d\u0442\u043d\u043e\u0441\u0442 (\u0430 \u0432\u0435\u0440\u043e\u044f\u0442\u043d\u043e \u0438 \u043d\u0430 \u0438\u0437\u043c\u0430\u043c\u0430) \u0438\u0441\u0442\u0438\u043d\u0430\u0442\u0430 \u0431\u0430\u0432\u043d\u043e \u0438\u0437\u043b\u0438\u0437\u0430 \u043d\u0430\u044f\u0432\u0435. \u0421\u043a\u043e\u0440\u043e \u043c\u043e\u0436\u0435 \u0434\u0430 \u0441\u0435 \u043e\u043a\u0430\u0436\u0435, \u0447\u0435 \u043b\u0435\u043a\u0430\u0440\u0441\u0442\u0432\u0430\u0442\u0430 \u043d\u0430 \u0431\u0430\u0431\u0430 \u0432\u0438 (\u0441\u0440\u0435\u0434 \u043a\u043e\u0438\u0442\u043e \u0441\u0435 \u043e\u0442\u043a\u0440\u043e\u044f\u0432\u0430\u0442 \u0430\u0441\u043f\u0438\u0440\u0438\u043d\u044a\u0442 \u0438 \u0441\u043e\u0434\u0430\u0442\u0430 \u0437\u0430 \u0445\u043b\u044f\u0431) \u0441\u0430 \u043f\u043e-\u0441\u0438\u043b\u043d\u0438 \u043e\u0442 \u043f\u043e\u0441\u043b\u0435\u0434\u043d\u0438\u0442\u0435 &#8222;\u043f\u043e\u0441\u0442\u0438\u0436\u0435\u043d\u0438\u044f&#8220; \u043d\u0430 \u043c\u0435\u0434\u0438\u0446\u0438\u043d\u0430\u0442\u0430, \u0434\u043e\u0440\u0438 \u0441\u0440\u0435\u0449\u0443 \u043d\u0435\u0449\u043e \u0442\u043e\u043b\u043a\u043e\u0432\u0430 \u0441\u0435\u0440\u0438\u043e\u0437\u043d\u043e \u043a\u0430\u0442\u043e \u0440\u0430\u043a\u0430!<\/p>\n\n\n\n<p><a href=\"https:\/\/www.nature.com\/articles\/s41587-019-0377-7\">https:\/\/www.nature.com\/articles\/s41587-019-0377-7<\/a><\/p>\n\n\n\n<p>\u201c\u2026We next tested ABP-LOXCAT in a model of&nbsp;<strong>drug-induced&nbsp;acute mitochondrial dysfunction using metformin<\/strong>, a mitochondrial complex I inhibitor[29]. Intraperitoneal (i.p.)&nbsp;<strong>injection of<\/strong>&nbsp;300mg kg\u22121 of&nbsp;<strong>metformin elevated the blood lactate:pyruvate ratio by 1.5-fold<\/strong>&nbsp;(P=0.0003) in 1h (Fig. 4d).\u201d<\/p>\n\n\n\n<p><a href=\"http:\/\/cancerres.aacrjournals.org\/content\/69\/6\/2260?ijkey=d178626fe1573d91eed32b4cf3a7927185de7699&amp;keytype2=tf_ipsecsha\">http:\/\/cancerres.aacrjournals.org\/content\/69\/6\/2260?ijkey=d178626fe1573d91eed32b4cf3a7927185de7699&amp;keytype2=tf_ipsecsha<\/a><\/p>\n\n\n\n<p><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30755444\">https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30755444<\/a><\/p>\n\n\n\n<p>\u201c\u2026Unlike normal cells,&nbsp;<strong>cancer cells can adapt to survive in low pH environments through increased glycolytic activity and expression of proton transporters that normalize intracellular pH<\/strong>.&nbsp;<strong>Acidosis-driven adaptation also triggers the emergence of aggressive tumor cell<\/strong>&nbsp;subpopulations that exhibit increased invasion, proliferation, and drug resistance (<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-4\">4\u20137<\/a>).&nbsp;<strong>Acidosis also promotes immune escape, which maintains tumor growth<\/strong>&nbsp;(<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-8\">8<\/a>).\u201d<\/p>\n\n\n\n<p>\u201c\u2026Transcriptome-wide studies suggest that tumor stressors such as hypoxia, nutrient starvation, and lactate acidosis can each regulate gene expression at the transcriptional and posttranscriptional levels&nbsp;<em>in vitro<\/em>&nbsp;(<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-12\">12\u201314<\/a>). For instance,&nbsp;<strong>low extracellular pH induces increased histone deacetylation, thereby influencing the expression of certain stress responsive genes and concomitantly contributing to normalization of intracellular pH through the enhanced release of acetate anions that are co-exported with protons through monocarboxylate transporters<\/strong>&nbsp;(<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-15\">15, 16<\/a>). However, how these changes influence transcriptome dynamics is not well understood, nor is it clear whether changes in gene expression arising from such stresses&nbsp;<em>in vitro<\/em>&nbsp;also correlate with those induced by equivalent physiologic stressors&nbsp;<em>in vivo<\/em>.\u201d<\/p>\n\n\n\n<p>To confirm that pHLIP reliably labeled acidic tumor areas, we evaluated its overlap relative to two additional markers associated with low extracellular pH: expression of CA9 and of plasma membrane-localized LAMP2 (PM-LAMP2; refs.&nbsp;<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-2\">2, 29, 30<\/a>). CA9 is a major transporter that contributes to extracellular acidification through reversible hydration of carbon dioxide to bicarbonate and protons.&nbsp;<strong>CA9 expression significantly correlated with areas of pHLIP retention at cell membranes in both the primary tumor (<\/strong><a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#F1\"><strong>Fig. 1C<\/strong><\/a><strong>) and metastatic lesions&nbsp;<\/strong>(Supplementary Fig. S1D). Given the extensive overlap with, and similar patterns of CA9 expression (<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#F1\">Fig. 1D<\/a>; Supplementary Fig. S1E) relative to pHLIP positive cells in the mouse model, we used CA9 as a surrogate to label cells in acidic areas in human tumor tissues. Similar to the mouse tumors, the&nbsp;<strong>CA9 was enriched at tumor-stroma interfaces in human tumors<\/strong>&nbsp;(Supplementary Fig. S1F).<\/p>\n\n\n\n<p>PM-LAMP2 indicates&nbsp;<strong>cellular adaptation to chronic acidosis<\/strong>&nbsp;(<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-2\">2, 31<\/a>). PM-LAMP2 overlapped significantly with pHLIP labeled cells (Supplementary Fig. S2A) and most cells with PM-LAMP2 were proximal to the&nbsp;<strong>tumor\u2013stroma interface confirming that it is acidic<\/strong>&nbsp;(Supplementary Fig. S2B). Similarly, in human IDC tumors,&nbsp;<strong>cells expressing CA9 significantly overlapped with cells exhibiting PM-LAMP2<\/strong>&nbsp;(Supplementary Fig. S2C and S2D). Therefore,&nbsp;<strong>areas containing pHLIP labeled cells or cells expressing high levels of CA9 likely correspond to cellular areas exposed to acidic conditions&nbsp;<em>in vivo<\/em><\/strong>.<\/p>\n\n\n\n<p>\u201c\u2026<strong>To mimic increased glycolysis conditions in culture, we used metformin, a drug that inhibits the complex I of mitochondria and therefore forces excessive lactate production<\/strong>&nbsp;(<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-44\">44<\/a>). As expected,&nbsp;<strong>metformin addition increased the amount of lactate in the media and acidified the media<\/strong>&nbsp;(<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#F5\">Fig. 5C\u2032<\/a>).&nbsp;<strong>Metformin addition also induced the pattern of low pH-induced splicing<\/strong>, which were blocked by addition of HEPES (<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#F5\">Fig. 5C<\/a>). Lactate content remained increased under hypoxic or lactate acidosis conditions with or without HEPES buffering (Supplementary Fig. S5C and S5D). These results indicate that, at least for the splicing events tested,&nbsp;<strong>exposure to extracellular acidity is sufficient to induce the observed changes, while hypoxia-induced changes in HIF expression or increased lactate are dispensable<\/strong>.\u201d<\/p>\n\n\n\n<p>\u201c\u2026To evaluate the pH responsiveness of the candidate splicing events&nbsp;<em>in vivo<\/em>, we examined the events in&nbsp;<strong>tumors collected from mice that received regular or bicarbonate water<\/strong>. As before,&nbsp;<strong>consumption of bicarbonate water was sufficient to reduce tumor acidity<\/strong>, evident by the reduction of pHLIP-localization in cells from those tumors relative to control (<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#F7\">Fig. 7A\u2013A\u2032<\/a>),&nbsp;<strong>and to reduce lung metastasis<\/strong>&nbsp;(<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-26\">26<\/a>). In addition, the percentage of Mena<sup>INV<\/sup>&nbsp;positive cells was significantly reduced in those tumors (<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#F7\">Fig. 7A\u2032\u2013A\u2033<\/a>). To examine the pH-responsive splicing candidates&nbsp;<em>in vivo<\/em>, tumors from control or treated mice were analyzed by qPCR analysis. Compared with the control samples, in&nbsp;<strong>tumors from PyMT mice that consumed bicarbonate water the inclusion ratio of the INV exon of Mena was significantly reduced. Similarly, the DOCK7 exon 23 and DLG1 exon 6 trended toward increased ratios, following the expected directionality<\/strong>, however, in these cases the changes were not statistically significant (<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#F7\">Fig. 7B<\/a>). The effect of buffering on pH-responsive exons was also evaluated in a xenograft model derived from MDA-MB-231 cells. In line with the findings in the MMTV-PyMT tumors,&nbsp;<strong>the appearance of all candidate pH-responsive splicing events was significantly attenuated in tumors collected from bicarbonate water treated group<\/strong>&nbsp;in the xenograft model (<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#F7\">Fig. 7C<\/a>). These data indicate that&nbsp;<strong>alteration in the extracellular acidity&nbsp;<em>in vivo<\/em>&nbsp;directly influences the expression of the pH-responsive signature<\/strong>.\u201d<\/p>\n\n\n\n<p>\u201c\u2026We characterized the spatial characteristics of acidic tumor microenvironment using pHLIP technology, and&nbsp;<strong>demonstrated that tumor\u2013stroma interfaces are acidic and that cells within the acidic front are invasive and proliferative<\/strong>. We found that&nbsp;<strong>exposure to low extracellular pH&nbsp;<em>in vitro<\/em>modulates RNA metabolism,<\/strong>&nbsp;particularly RNA splicing, and identified a potential role for a family of RBPs with affinity for AU-rich motif, in the pH-induced transcriptomic signature.&nbsp;<strong>The low-pH signature indicated extensive changes in alternative splicing and was notably enriched for splicing of genes implicated in regulation of adhesion and cell migration<\/strong>. Although the global regulation of RNA splicing in response to acidosis&nbsp;<em>in vivo<\/em>&nbsp;remains to be determined, we demonstrated that a set of functionally important candidate splicing events is similarly pH responsive&nbsp;<em>in vitro<\/em>&nbsp;and&nbsp;<em>in vivo<\/em>. The pH-responsive splicing of Mena and CD44 was sensitive to pH-induced histone deacetylation&nbsp;<em>in vitro,<\/em>&nbsp;<strong>demonstrating a link between chromatin deacetylation and modulation of RNA splicing in response to extracellular acidity<\/strong>. These findings provide new molecular insight into one way in which acidosis contributes to local&nbsp;<strong>transcriptomic alterations that promote prometastatic phenotypes<\/strong>.\u201d<\/p>\n\n\n\n<p><strong>Consistent with its well established role in local invasion and malignant progression<\/strong>&nbsp;(<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-7\">7, 46<\/a>),&nbsp;<strong>we found that acidosis is enriched adjacent to tumor\u2013stroma interfaces<\/strong>&nbsp;in addition to areas within hypoxic cores.&nbsp;<strong>Acidosis in well-oxygenated areas can be caused by adaptation to increased aerobic glycolysis or oxidative phosphorylation<\/strong>&nbsp;(<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-1\">1, 47<\/a>). LDHA expression was indeed enriched within a subset of acidic cellular areas at the tumor\u2013stroma interfaces (<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-3\">3, 32<\/a>). Acidic regions, however, were not restricted to sites of increased glycolysis marked by LDHA, indicating that acidosis may also be induced by other means such as protons generated through oxidative phosphorylation.&nbsp;<strong>Prolonged exposure to extracellular acidification shifts cancer cell metabolic reprogramming towards reactive oxygen species homeostasis and therefore promotes proliferation and aggressive phenotypes under harsh conditions<\/strong>. An example of&nbsp;<strong>such mechanism is mediated through<\/strong>&nbsp;a balance between histone deacetylation, mitochondrial hyper acetylation, and&nbsp;<strong>increased fatty acid oxidation<\/strong>&nbsp;(<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-16\">16<\/a>). Consistently, we observed that cells within low pH areas express high levels of HDAC and Ki-67&nbsp;<em>in vivo<\/em>. Our results build upon previous reports on the correlation of extracellular acidity and local growth (<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-7\">7<\/a>) and improve our understanding of the distribution of the acidic microenvironment relative to hallmarks of tumor progression.<\/p>\n\n\n\n<p>The inclusion of exon 19 of CD44 generates a short isoform of CD44 with a truncated cytoplasmic tail. Its expression&nbsp;<em>in vitro<\/em>&nbsp;is upregulated in multidrug-resistant MCF-7\/Adr cells, and also affects cell invasion through the Ras\/MAPK signaling pathway (<a href=\"http:\/\/cancerres.aacrjournals.org\/content\/79\/8\/1952.long#ref-37\">37<\/a>).&nbsp;<strong>Here we demonstrate both&nbsp;<em>in vivo<\/em>&nbsp;and&nbsp;<em>in vitro<\/em>&nbsp;that acidosis is necessary and sufficient to drive the expression of these isoforms in both mouse and human tumors<\/strong>. These examples indicate that&nbsp;<strong>acidic microenvironment induces the expression of isoforms of genes associated with malignancy<\/strong>; however, it remains to be established if acidosis&nbsp;<em>in vivo<\/em>&nbsp;induces a global transcriptomic rewiring that influences splicing similar to the phenomenon observed&nbsp;<em>in vitro<\/em>.<\/p>\n\n\n\n<p>Together, our results lead us to propose that&nbsp;<strong>acidosis, an intrinsic feature of the microenvironment, is enriched at the tumor invasive fronts and triggers adaptive changes in gene expression and splicing<\/strong>&nbsp;that are potentially controlled through a specific set of RBPs and downstream of pH-induced chromatin modifications. Our study provides new insights into how&nbsp;<strong>acidosis contributes to alterations underlying malignant progression<\/strong>. Understanding how acidosis evokes transcriptomic changes that confer aggressive tumor phenotypes will provide therapeutically valuable insight.<\/p>\n\n\n\n<p>\u0418\u0437\u0442\u043e\u0447\u043d\u0438\u043a:<\/p>\n\n\n\n<p><a href=\"http:\/\/haidut.me\/?p=171\">http:\/\/haidut.me\/?p=171<\/a><\/p>\n\n\n\n<p><\/p>\n\n\n<ul class=\"wp-block-latest-posts__list wp-block-latest-posts\"><li><a class=\"wp-block-latest-posts__post-title\" href=\"https:\/\/xenobg.com\/en\/%d1%80%d0%b5%d0%b2%d0%be%d0%bb%d1%8e%d1%86%d0%b8%d0%be%d0%bd%d0%b5%d0%bd-%d0%bf%d0%be%d0%b3%d0%bb%d0%b5%d0%b4-%d0%b2%d1%8a%d1%80%d1%85%d1%83-%d1%80%d0%b0%d0%ba%d0%b0-%d0%bc%d0%b5%d1%82%d0%b0%d0%b1\/\">\u0420\u0435\u0432\u043e\u043b\u044e\u0446\u0438\u043e\u043d\u0435\u043d \u043f\u043e\u0433\u043b\u0435\u0434 \u0432\u044a\u0440\u0445\u0443 \u0440\u0430\u043a\u0430: \u041c\u0435\u0442\u0430\u0431\u043e\u043b\u0438\u0442\u0435\u043d, \u0430 \u043d\u0435 \u0441\u0430\u043c\u043e \u0433\u0435\u043d\u0435\u0442\u0438\u0447\u0435\u043d \u043f\u0440\u043e\u0431\u043b\u0435\u043c<\/a><\/li>\n<li><a class=\"wp-block-latest-posts__post-title\" href=\"https:\/\/xenobg.com\/en\/hidroksiapatit-v-oralnata-grizha\/\">\u0425\u0438\u0434\u0440\u043e\u043a\u0441\u0438\u0430\u043f\u0430\u0442\u0438\u0442 \u0432 \u043e\u0440\u0430\u043b\u043d\u0430\u0442\u0430 \u0433\u0440\u0438\u0436\u0430: \u041f\u0440\u0435\u0433\u043b\u0435\u0434 \u043d\u0430 \u043f\u043e\u043b\u0437\u0438\u0442\u0435, \u043c\u0435\u0445\u0430\u043d\u0438\u0437\u043c\u0430 \u0438 \u0441\u0440\u0430\u0432\u043d\u0435\u043d\u0438\u0435 \u0441 \u0444\u043b\u0443\u043e\u0440\u0438\u0434\u0430<\/a><\/li>\n<li><a class=\"wp-block-latest-posts__post-title\" href=\"https:\/\/xenobg.com\/en\/kolko-presni-portokala-sa-vi-neobhodimi-za-da-izchistite-chernia-si-drob-ot-maznini\/\">\u041a\u043e\u043b\u043a\u043e \u043f\u0440\u0435\u0441\u043d\u0438 \u043f\u043e\u0440\u0442\u043e\u043a\u0430\u043b\u0430 \u0441\u0430 \u0432\u0438 \u043d\u0435\u043e\u0431\u0445\u043e\u0434\u0438\u043c\u0438, \u0437\u0430 \u0434\u0430 \u0438\u0437\u0447\u0438\u0441\u0442\u0438\u0442\u0435 \u0447\u0435\u0440\u043d\u0438\u044f \u0441\u0438 \u0434\u0440\u043e\u0431 \u043e\u0442 \u043c\u0430\u0437\u043d\u0438\u043d\u0438?<\/a><\/li>\n<li><a class=\"wp-block-latest-posts__post-title\" href=\"https:\/\/xenobg.com\/en\/hronichniyat-stres-ponizhava-dopamina-i-prichinyava-psihichni-zabolyavania\/\">\u0425\u0440\u043e\u043d\u0438\u0447\u043d\u0438\u044f\u0442 \u0441\u0442\u0440\u0435\u0441 \u043f\u043e\u043d\u0438\u0436\u0430\u0432\u0430 \u0434\u043e\u043f\u0430\u043c\u0438\u043d\u0430 \u0438 \u043f\u0440\u0438\u0447\u0438\u043d\u044f\u0432\u0430 \u043f\u0441\u0438\u0445\u0438\u0447\u043d\u0438 \u0437\u0430\u0431\u043e\u043b\u044f\u0432\u0430\u043d\u0438\u044f<\/a><\/li>\n<li><a class=\"wp-block-latest-posts__post-title\" href=\"https:\/\/xenobg.com\/en\/estrogenat-i-kortizolat-a-ne-androgenite-potiskat-imuniteta\/\">\u0415\u0441\u0442\u0440\u043e\u0433\u0435\u043d\u044a\u0442 \u0438 \u043a\u043e\u0440\u0442\u0438\u0437\u043e\u043b\u044a\u0442, \u0430 \u043d\u0435 \u0430\u043d\u0434\u0440\u043e\u0433\u0435\u043d\u0438\u0442\u0435, \u043f\u043e\u0442\u0438\u0441\u043a\u0430\u0442 \u0438\u043c\u0443\u043d\u0438\u0442\u0435\u0442\u0430<\/a><\/li>\n<\/ul>","protected":false},"excerpt":{"rendered":"<p>\u041a\u0430\u043a\u0442\u043e \u043c\u043d\u043e\u0437\u0438\u043d\u0430 \u0447\u0438\u0442\u0430\u0442\u0435\u043b\u0438 \u0437\u043d\u0430\u044f\u0442, \u0438\u0437\u043f\u043e\u043b\u0437\u0432\u0430\u043d\u0435\u0442\u043e \u043d\u0430 \u0441\u043e\u0434\u0430 \u0431\u0438\u043a\u0430\u0440\u0431\u043e\u043d\u0430\u0442 \u0437\u0430 \u043b\u0435\u0447\u0435\u043d\u0438\u0435 \u043d\u0430 \u0440\u0430\u043a &nbsp;\u0431\u0435\u0448\u0435 \u043e\u0431\u044f\u0432\u0435\u043d\u043e \u0437\u0430 &#8222;\u0448\u0430\u0440\u043b\u0430\u0442\u0430\u043d\u0441\u043a\u0430 \u043c\u0435\u0434\u0438\u0446\u0438\u043d\u0430&#8220; \u043e\u0442 \u043c\u043d\u043e\u0433\u043e \u0433\u043e\u0432\u043e\u0440\u0438\u0442\u0435\u043b\u0438 \u043d\u0430 \u043e\u0444\u0438\u0446\u0438\u0430\u043b\u043d\u0430\u0442\u0430 \u043c\u0435\u0434\u0438\u0446\u0438\u043d\u0430, \u043a\u0430\u043a\u0442\u043e \u0438 \u043e\u0442 \u043d\u044f\u043a\u043e\u043b\u043a\u043e &#8222;\u043d\u0430\u0431\u043b\u044e\u0434\u0430\u0432\u0430\u0449\u0438&#8220; \u0433\u0440\u0443\u043f\u0438. \u0415\u0442\u043e \u043d\u044f\u043a\u043e\u0438 \u043b\u0438\u043d\u043a\u043e\u0432\u0435 \u0441 \u0438\u043d\u0444\u043e\u0440\u043c\u0430\u0446\u0438\u044f, \u043a\u043e\u044f\u0442\u043e \u0442\u043e\u0442\u0430\u043b\u043d\u043e \u043e\u0442\u0440\u0438\u0447\u0430 \u0443\u043f\u043e\u0442\u0440\u0435\u0431\u0430\u0442\u0430 \u043d\u0430 \u0441\u043e\u0434\u0430 \u0431\u0438\u043a\u0430\u0440\u0431\u043e\u043d\u0430\u0442 \u043f\u0440\u0438 \u0440\u0430\u043a. https:\/\/scienceblog.cancerresearchuk.org\/2014\/03\/24\/dont-believe-the-hype-10-persistent-cancer-myths-debunked\/#fungus \u041d\u044f\u043a\u043e\u0438 \u043e\u0442 \u0442\u0432\u044a\u0440\u0434\u0435\u043d\u0438\u044f\u0442\u0430 \u043d\u0430 \u043f\u0440\u0438\u0432\u044a\u0440\u0436\u0435\u043d\u0438\u0446\u0438\u0442\u0435 \u043d\u0430 \u0441\u043e\u0434\u0430\u0442\u0430 \u0437\u0430 \u0445\u043b\u044f\u0431 \u043d\u0435 \u0441\u0430 [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_et_pb_use_builder":"","_et_pb_old_content":"","_et_gb_content_width":"","advgb_blocks_editor_width":"","advgb_blocks_columns_visual_guide":"","_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"_uf_show_specific_survey":0,"_uf_disable_surveys":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[850,949],"tags":[329,1040,1001,201,802,1130,1097],"class_list":["post-23688","post","type-post","status-publish","format-standard","hentry","category-haidut","category-949","tag-haidut","tag-1040","tag-1001","tag-201","tag-802","tag-1130","tag-1097"],"yoast_head":"<!-- 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