{"id":12507,"date":"2016-12-17T03:39:37","date_gmt":"2016-12-17T03:39:37","guid":{"rendered":"http:\/\/www.kurzweilai.net\/?p=291136"},"modified":"2016-12-17T03:39:37","modified_gmt":"2016-12-17T03:39:37","slug":"how-diabetes-drug-metformin-prevents-suppresses-cancer-growth","status":"publish","type":"post","link":"https:\/\/hoo.central12.com\/fugic\/2016\/12\/17\/how-diabetes-drug-metformin-prevents-suppresses-cancer-growth\/","title":{"rendered":"How diabetes drug metformin prevents, suppresses cancer growth"},"content":{"rendered":"
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Metformin growth inhibition process (credit: Lianfeng Wu et al.\/Cell)<\/p><\/div>\n

A team of Massachusetts General Hospital (MGH)<\/a> and Harvard Medical School investigators has identified a pathway that appears to underlie the apparent ability of the diabetes drug metformin to both block the growth of human cancer cells and extend the lifespan of the\u00a0C.elegans<\/em>\u00a0roundworm.<\/p>\n

That finding implies that this single genetic pathway may play an important role in a wide range of organisms — including humans.<\/p>\n

\u201cWe found that metformin reduces the traffic of molecules into and out of the nucleus — the \u2018information center\u2019 of the cell,\u201d says Alexander Soukas, MD, PhD<\/a>, of the MGH\u00a0Center for Human Genetic Research<\/a>, senior author of the study, published in the Thursday, Dec. 15 issue of\u00a0Cell<\/em>.<\/p>\n

\u201cReduced nuclear traffic translates into the ability of the drug to block cancer growth and, remarkably, is also responsible for metformin\u2019s ability to extend lifespan,” he said. “By shedding new light on metformin\u2019s health-promoting effects, these results offer new potential ways that we can think about treating cancer and increasing healthy aging.\u201d<\/p>\n

Several studies have suggested that individuals taking metformin have a reduced risk of developing certain cancers and of dying from cancers that do develop. Current clinical trials are testing the impact of metformin on cancers of the breast, prostate and pancreas; and several research groups are working to identify its molecular targets.<\/p>\n

How Metformin lowers blood glucose — and growth <\/strong><\/p>\n

Metformin\u2019s ability to lower blood glucose in patients with type 2 diabetes appears to result from the drug\u2019s effects on the liver. The drug reduces the liver’s ability to produce glucose for release into the bloodstream. Metformin has been thought to block the activity of mitochondria — structures that serve as the powerhouse of the cell.<\/p>\n

But Soukas says more recent information suggests the mechanism is more complex. The Soukas team found a genetic pathway that slows the growth and extends the lifespan of\u00a0C.elegans<\/em> roundworms. That suggests that the roundworm could serve as a model for investigating the drug\u2019s effects on cancer.*<\/p>\n

\u201cAmazingly, this pathway operates identically, whether in the worm or in human cancer cells,\u201d says Soukas, who is an assistant professor of Medicine at Harvard Medical School. \u201cDetermining exactly how [it] slows cell growth will provide additional insights into novel therapeutic targets for cancer and possibly ways to manipulate the pathway to promote healthy aging.\u201d** <\/em><\/p>\n

Support for this study includes National Institutes of Health grants, a Broad Institute SPARC Grant, and the Ellison Medical Foundation New Scholar in Aging Award.<\/p>\n

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Metformin both suppresses cancer cell growth and promotes organismal longevity through a key transcriptional target that is induced through inhibition of mitochondrial respiration and modulation of mTOR signaling. (credit: Lianfeng Wu et al.\/Cell)<\/p><\/div>\n

* The Soukas team’s experiments found that metformin\u2019s action against cancer relies on two elements of a single genetic pathway \u2013 the nuclear pore complex, which allows the passage of molecules into and out of the nucleus, and an enzyme called ACAD10. <\/em><\/p>\n

Basically, metformin\u2019s suppression of mitochondrial activity reduces cellular energy, restricting the traffic of molecules through the nuclear pore. This shuts off an important cellular growth molecule called mTORC1, resulting in activation of ACAD10, which both slows the growth and extends the lifespan of\u00a0C.elegans.<\/em><\/p>\n

In human melanoma and pancreatic cancer cells, the investigators confirmed that application of drugs in the metformin family induced ACAD10 expression, an effect that depended on the function of the nuclear pore complex. <\/em><\/p>\n

Without the complete signaling pathway \u2013 from mitochondrial suppression, through nuclear pore restriction to ACAD10 expression \u2013 cancer cells were no longer sensitive to the effects of metformin-like drugs.<\/em><\/p>\n

** \u201cOur experiments showed two very important things: if we force the nuclear pore to remain open or if we permanently shut down ACAD10, metformin can no longer block the growth of cancer cells. That suggests that the nuclear pore and ACAD10 may be manipulated in specific circumstances to prevent or even treat certain cancers.\u201d<\/em><\/p>\n

The essential contribution of ACAD10 to metformin\u2019s anticancer action is intriguing, Soukas adds, because the only published study on ACAD10 function tied a variant in the gene to the increased risk of type 2 diabetes in Pima Indians, suggesting that ACAD10 also has a role in the drug\u2019s antidiabetes action. \u201cWhat ACAD10 does is a great mystery that we are greatly interested in solving,\u201d he says.\u00a0<\/em><\/p>\n

\n

Abstract of\u00a0An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer<\/em><\/strong><\/p>\n

Metformin has utility in cancer prevention and treatment, though the mechanisms for these effects\u00a0remain elusive. Through genetic screening in\u00a0C.\u00a0elegans<\/em>, we uncover two metformin response elements: the nuclear pore complex (NPC) and acyl-CoA dehydrogenase family member-10 (ACAD10). We demonstrate that biguanides inhibit growth by\u00a0inhibiting mitochondrial respiratory capacity, which restrains transit of the RagA-RagC GTPase heterodimer through the NPC. Nuclear exclusion renders RagC incapable of gaining the GDP-bound state necessary to stimulate mTORC1. Biguanide-induced inactivation of mTORC1 subsequently inhibits growth through transcriptional induction of ACAD10. This ancient metformin response pathway is conserved from worms to humans. Both restricted nuclear pore transit and upregulation of ACAD10 are required for biguanides to reduce viability in melanoma and pancreatic cancer cells, and to extend\u00a0C.\u00a0elegans<\/em>\u00a0lifespan. This pathway provides a unified mechanism by which metformin kills cancer cells and extends lifespan, and illuminates potential cancer targets.<\/p>\n","protected":false},"excerpt":{"rendered":"

A team of Massachusetts General Hospital (MGH) and Harvard Medical School investigators has identified a pathway that appears to underlie the apparent ability of the diabetes drug metformin to both block the growth of human cancer cells and extend the lifespan of the C.elegans roundworm. That finding implies that this single genetic pathway may play an important […]<\/p>\n","protected":false},"author":13,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[45,43],"tags":[],"class_list":["post-12507","post","type-post","status-publish","format-standard","hentry","category-biomedlongevity","category-news"],"_links":{"self":[{"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/posts\/12507"}],"collection":[{"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/users\/13"}],"replies":[{"embeddable":true,"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/comments?post=12507"}],"version-history":[{"count":1,"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/posts\/12507\/revisions"}],"predecessor-version":[{"id":12508,"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/posts\/12507\/revisions\/12508"}],"wp:attachment":[{"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/media?parent=12507"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/categories?post=12507"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/tags?post=12507"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}