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.