Metformin limits the adipocyte tumor-promoting effect on ovarian cancer.

Calvin Tebbe,Shailendra Giri,Ramandeep Rattan,Adnan R Munkarah,Kalli Sarigiannis,Sajad A Dar,Jasdeep Chhina

doi:10.18632/oncotarget.2012

Abstract

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.

Highlights

Ovarian cancer is the fifth leading cause of cancer death in women and the most fatal of all gynecological cancers [1]
We investigated whether metformin can regulate the adipocyte-adipokine stimulated ovarian cancer growth and impact the initial steps of ovarian cancer metastasis
To examine the effect of adipocyte conditioned media on the growth of ID8 mouse ovarian tumor cells, ID8 cells were exposed with Rosewell Park Memorial Institute (RPMI) media and adipo CM at various ratios (75:25; 50:50; 0:100)

Summary

INTRODUCTION

Ovarian cancer is the fifth leading cause of cancer death in women and the most fatal of all gynecological cancers [1]. AMPK by virtue of its metabolic regulatory effect regulates adipogenesis and lipolysis [38, 39], placing it in a unique position to alter the adipocyte generated microenvironment for the tumor cells. Both adipogenesis and lipolysis have been shown to aid the ovarian tumor cells in proliferation and metastasis [6]. It would be rational to design and test therapies that can target this first step in the ovarian cancer metastasis and may prevent its further spread With this objective, we investigated whether metformin can regulate the adipocyte-adipokine stimulated ovarian cancer growth and impact the initial steps of ovarian cancer metastasis. Our study shows that metformin has the ability to inhibit adipogenesis and the ovarian tumor promoting effects driven by adipocytes

RESULTS

DISCUSSION

MATERIALS AND METHODS

Conflict of Interest