Tumors

The risk of fatal cancer development increases exponentially with age, and around 60% of cancers are diagnosed in people 65 years or older. Activation of oncogenes and shutdowns of tumor suppressor genes result in reprogrammed energy metabolism and uncontrolled cell growth and division.47 Hence, it makes sense that over-activation of mTORC1 signaling has been observed in many types of cancer such as lymphoma, endometrial cancer, and renal cell carcinoma.48–50 Activated mTORC1 promotes aerobic glycolysis by increasing the amount of hypoxia inducible factor (HIF)-1α, a transcription factor that is associated with metastasis by promoting angiogenesis responding to hypoxia.51 It also indirectly upregulates genes involved in lipogenesis by phosphorylating Lipin-1 and S6K-1, which activates SREBP-1, a lipogenic transcription factor.52,53 Additionally, phosphorylating S6K1 enhances biosynthesis of purine and pyrimidine, two amino acids required for cancer cell proliferation.54As the potent inhibitor of mTORC1, rapamycin can put a brake on the defective tumor metabolism and has been investigated as a promising drug to treat cancer. In 2002, rapamycin was first reported to have antineoplastic properties in mice by suppressing cancer metastasis and angiogenesis.55 Since then, overwhelming in vivo and in vitro studies have reported that rapamycin and its derivatives have the potential of ameliorating cancer onset and development, and hundreds of clinical trials have been conducted to test monotherapy or combination therapies of rapamycin.24,56 For instance, rapamycin treatment decreased both phenotypic progression of tumor and tumor size in mice exposed to the tobacco carcinogen NNK and had lung cancer.57 Nevertheless, the actual clinical benefits of rapamycin and rapalogs have been mostly modest.58,59 In a study using transgenic HER-2/neu cancer prone mice, although rapamycin did not extend the lifespan of the mice with established tumor, it effectively delayed spontaneous tumor onset in others and extended their lifespan, suggesting its potential as a measure to prevent cancer.56
Multiple studies have also supported that the growth inhibition caused by metformin’s interaction with the AMPK/mTOR pathway to be effective against various cancers including lung cancer, breast cancer, and colorectal cancer.60 Metformin delayed the first tumor onset by 22% and 25% respectively in female mice at the age of 3 months and 9 months.61 Furthermore, metformin inhibited NNK-induced lung cancer cell proliferation in mice by decreasing the levels of circulating insulin and IGF-1, which suppressed the IIS pathway and downregulated the downstream PI3K-Akt and mTOR signaling pathway (Fig. 1).62 In endometrial cancer cells, metformin significantly reduced the levels of Ki-67, an indicator of tumor progression, topoisomerase IIα, associated with DNA instability, and phospho-ribosomal protein S6 and phospho-ERK 1/2, both of which activated by mTOR. Significantly increased AMPK and p27 levels and subsequent cell cycle inhibition were also observed.63 H19 is found in almost all cancer cells. Genome-scale DNA methylation profiling showed that tumor promoting pathway genes became repressed and genes involved in neuronal development, cell morphology, and intracellular communication were activated after metformin treatment. Interestingly, the H19 gene was also inactivated, suggesting a feed-forward response to continuously suppress H19 can be established by metformin.19 In addition, the 11 metformin-induced differentially methylated CpG sites mentioned earlier were related to multiple tumor-related genes: SIX3 is downregulated in lung cancer due to promoter methylation, which was rescued by metformin. POFUT2 is linked to glioblastoma and adenocarcinoma. MUC4 is implicated in pancreatic cancer. KIAA1614 is related to colon cancer. Lastly, UPF1 is associated with genome stability. The differentially methylated regions included the gene EPHB1, whose underexpression leads to gastric carcinoma and invasion of colorectal cancer cells, and SERP2, which is positively correlated with BMI and abnormal glucose tolerance as well as colorectal cancer. Pathway enrichment analysis found association between the CpG sites and the unfolded protein response, which is involved in metformin-induced apoptosis in acute lymphoblastic leukemia.22 In 2005, a case control study first discovered reduced risk of cancer associated with metformin in diabetic patients.64 Compared with people who took sulfonylureas, insulin, and other anti-diabetic drugs, metformin users had a significantly lower risk of cancer (Hazard Ratio [HR] 0.63, 95% Confidence Interval [CI] [0.53-0.75]).65 Diabetic patients who took metformin also had 7% less chance of getting hepatocellular cancer for each incremental year they took metformin, and it was attributed to inhibited proliferation and cell cycle arrest induced by metformin in the hepatocytes.66 Nevertheless, there are studies that do not support metformin’s beneficial role in cancer. Evidence from randomized control trials has been large inconclusive.67,68 Additionally, in a study that compares metformin with rosiglitazone and sulfonylureas, metformin users did not show lower malignancy rates.69 Multiple meta-analyses also did not find any evidence showing metformin reduces cancer incidence.70,71 Work is still needed to resolve these inconsistencies.