Metformin, a diabetes drug, eliminates tumor-initiating hepatocellular carcinoma cells.
Metformin has been widely used as an oral drug for diabetes mellitus for approximately 60 years. Interestingly, recent reports showed that metformin exhibited an anti-tumor action in a wide range of malignancies including hepatocellular carcinoma (HCC). In the present study, we investigated its impact on tumor-initiating HCC cells. Metformin suppressed cell growth and induced apoptosis in a dose-dependent manner. Flow cytometric analysis showed that metformin treatment markedly reduced the number of tumor-initiating epithelial cell adhesion molecule (EpCAM)(+) HCC cells. Non-adherent sphere formation assays of EpCAM(+) cells showed that metformin impaired not only their sphere-forming ability, but also their self-renewal capability. Consistent with this, immunostaining of spheres revealed that metformin significantly decreased the number of component cells positive for hepatic stem cell markers such as EpCAM and α-fetoprotein. In a xenograft transplantation model using non-obese diabetic/severe combined immunodeficient mice, metformin and/or sorafenib treatment suppressed the growth of tumors derived from transplanted HCC cells. Notably, the administration of metformin but not sorafenib decreased the number of EpCAM(+) cells and impaired their self-renewal capability. As reported, metformin activated AMP-activated protein kinase (AMPK) through phosphorylation; however its inhibitory effect on the mammalian target of rapamycin (mTOR) pathway did not necessarily correlate with its anti-tumor activity toward EpCAM(+) tumor-initiating HCC cells. These results indicate that metformin is a promising therapeutic agent for the elimination of tumor-initiating HCC cells and suggest as-yet-unknown functions other than its inhibitory effect on the AMPK/mTOR pathway.
Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Tomoko
T
Saito
Tetsuhiro
T
Chiba
Kaori
K
Yuki
Yoh
Y
Zen
Motohiko
M
Oshima
Shuhei
S
Koide
Tenyu
T
Motoyama
Sadahisa
S
Ogasawara
Eiichiro
E
Suzuki
Yoshihiko
Y
Ooka
Akinobu
A
Tawada
Motohisa
M
Tada
Fumihiko
F
Kanai
Yuichi
Y
Takiguchi
Atsushi
A
Iwama
Osamu
O
Yokosuka
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy*; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D023041:Xenograft Model Antitumor Assays
D007004:Hypoglycemic Agents; D008687:Metformin