Metformin limits the adipocyte tumor-promoting effect on ovarian cancer
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Calvin Tebbe1, Jasdeep Chhina1, Sajad A. Dar1, Kalli Sarigiannis1, Shailendra Giri2, Adnan R. Munkarah1, and Ramandeep Rattan1
1 Division of Gynecology Oncology, Department of Women’s Health, Obstetrics and Gynecology, Henry Ford Hospital, Detroit, MI 48202, USA.
2 Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.
Ramandeep Rattan, email:
Keywords: ovarian cancer, 3T3L1 adipocytes, metformin, AMPK, ID8 cells, adipogenesis
Received: March 6, 2014 Accepted: May 26, 2014 Published: May 26, 2014
Omental adipocytes promote ovarian cancer by secretion of adipokines, cytokines and growth factors, and acting as fuel depots. We investigated if metformin modulates the ovarian cancer promoting effects of adipocytes. Effect of conditioned media obtained from differentiated mouse 3T3L1 preadipoctes on the proliferation and migration of a mouse ovarian surface epithelium cancer cell line (ID8) was estimated. Conditioned media from differentiated adipocytes increased the proliferation and migration of ID8 cells, which was attenuated by metformin. Metformin inhibited adipogenesis by inhibition of key adipogenesis regulating transcription factors (CEBPα, CEBPß, and SREBP1), and induced AMPK. A targeted Cancer Pathway Finder RT-PCR (real-time polymerase chain reaction) based gene array revealed 20 up-regulated and 2 down-regulated genes in ID8 cells exposed to adipocyte conditioned media, which were altered by metformin. Adipocyte conditioned media also induced bio-energetic changes in the ID8 cells by pushing them into a highly metabolically active state; these effects were reversed by metformin. Collectively, metformin treatment inhibited the adipocyte mediated ovarian cancer cell proliferation, migration, expression of cancer associated genes and bio-energetic changes. Suggesting, that metformin could be a therapeutic option for ovarian cancer at an early stage, as it not only targets ovarian cancer, but also modulates the environmental milieu.
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