Abstract
Metformin has demonstrated substantial potential for use in cancer treatments. Liver kinase B (LKB)-AMP-activated protein kinase (AMPK) and mTOR are reported to be the main targets of metformin in relation to its ability to prevent cancer cell proliferation. However, the role of metformin in the control of neoplastic cancer cell growth is possibly independent of LKB-AMPK and mTOR. Using C. elegans as a model, we found that the neuronal Q-cell divisions in L1-arrested worms were suppressed following metformin treatment in AMPK-deficient mutants, suggesting that the mechanism by which metformin suppresses these cell divisions is independent of AMPK. Our results showed that the mTOR pathway indeed played a role in controlling germ cell proliferation, but it was not involved in the neuronal Q-cell divisions occurring in L1-arrested worms. We found that the neuronal Q-cells divisions were held at G1/S cell stage by metformin in vivo. Additionally, we demonstrated that metformin could reduce the phosphorylation activity of BRAF and block the BRAF-MAPK oncogenesis pathway to regulate neuronal Q-cell divisions during L1 arrest. This work discloses a new mechanism by which metformin treatment acts to promote neuronal cancer prevention, and these results will help promote the study of the anticancer mechanisms underlying metformin treatments.
Highlights
Metformin, a first-line drug used in the treatment of type 2 diabetes, is reported to have potential benefits in cancer prevention and treatment [1,2,3,4]
We found that two genes control QR/L proliferation during L1 arrest: aak-2/ampk and daf-18/pten
We found that both metformin and rapamycin suppressed germ-cell proliferation duringduring
Summary
A first-line drug used in the treatment of type 2 diabetes, is reported to have potential benefits in cancer prevention and treatment [1,2,3,4]. Metformin can activate mTORC1 via lysosome-localized Rag GTPases directly bound to the Raptor subunit of mTORC1 [3,18] These studies suggest that the function of metformin might govern lysosome-LKB-AMPK and Rag-mTORC1 to control cancer cell proliferation. BRAF can be regulated by another ontogenetic protein, PP2A, to control the MEK-ERK pathway [30,31] This current study found that metformin could suppress cell proliferation even when AMPK was abolished, while the loss of BRAF eliminated the suppressive function of metformin towards the Q-cell divisions. BRAF, as opposed to AMPK and mTOR, might be the primary target of metformin for controlling neuroblastic cell proliferation In this regard, the further study of metformin function might help reveal the acute mechanisms involved in this drug’s ability to evoke anticancer signal transduction in animals
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