Metformin Limits the Adipocyte Tumor-promoting Effect on Ovarian Cancer

Overview

Journal Oncotarget

Specialty Oncology

Date 2014 Jun 28

PMID 24970804

Citations 51

Authors

Calvin Tebbe

Jasdeep Chhina

Sajad A Dar

Kalli Sarigiannis

Shailendra Giri

Adnan R Munkarah

Ramandeep Rattan

Affiliations

Soon will be listed here.

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.

Citing Articles

Targeting metabolism to enhance immunotherapy within tumor microenvironment.

Liang X, Chen X, Yan Y, Cheng A, Lin J, Jiang Y Acta Pharmacol Sin. 2024; 45(10):2011-2022.

PMID: 38811773 PMC: 11420344. DOI: 10.1038/s41401-024-01304-w.

Dietary phenolic compounds as promising therapeutic agents for diabetes and its complications: A comprehensive review.

Aryal D, Joshi S, Thapa N, Chaudhary P, Basaula S, Joshi U Food Sci Nutr. 2024; 12(5):3025-3045.

PMID: 38726403 PMC: 11077226. DOI: 10.1002/fsn3.3983.

Novel Adiponectin Receptor Agonist Inhibits Cholangiocarcinoma via Adenosine Monophosphate-activated Protein Kinase.

Bui K, Nguyen T, Barat S, Scholta T, Xing J, Bhuria V Curr Med Chem. 2024; 31(28):4534-4548.

PMID: 38361349 DOI: 10.2174/0109298673254969231122114107.

Adipocyte Microenvironment in Ovarian Cancer: A Critical Contributor?.

Mendes A, Freitas A, Vicente R, Vitorino M, Vaz Batista M, Silva M Int J Mol Sci. 2023; 24(23).

PMID: 38068912 PMC: 10706733. DOI: 10.3390/ijms242316589.

Stromal cells in the tumor microenvironment: accomplices of tumor progression?.

Zhao Y, Shen M, Wu L, Yang H, Yao Y, Yang Q Cell Death Dis. 2023; 14(9):587.

PMID: 37666813 PMC: 10477351. DOI: 10.1038/s41419-023-06110-6.

References

Minas V, Rolaki A, Kalantaridou S, Sidiropoulos J, Mitrou S, Petsas G . Intratumoral CRH modulates immuno-escape of ovarian cancer cells through FasL regulation. Br J Cancer. 2007; 97(5):637-45. PMC: 2360374. DOI: 10.1038/sj.bjc.6603918. View

Daval M, Foufelle F, Ferre P . Functions of AMP-activated protein kinase in adipose tissue. J Physiol. 2006; 574(Pt 1):55-62. PMC: 1817807. DOI: 10.1113/jphysiol.2006.111484. View

Nieman K, Romero I, Van Houten B, Lengyel E . Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim Biophys Acta. 2013; 1831(10):1533-41. PMC: 3742583. DOI: 10.1016/j.bbalip.2013.02.010. View

Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B . Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 2011; 71(7):2455-65. DOI: 10.1158/0008-5472.CAN-10-3323. View

Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L . Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007; 131(3):463-75. DOI: 10.1016/j.cell.2007.08.038. View

Chiu H, Sun G, Chen S, Wang H, Ho M, Chu C . Pre-existing Fas ligand (FasL) in cancer cells elicits tumor-specific protective immunity, but delayed induction of FasL expression after inoculation facilitates tumor formation. Mol Carcinog. 2012; 52(9):705-14. DOI: 10.1002/mc.21909. View

Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P . The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008; 27(25):3576-86. DOI: 10.1038/sj.onc.1211024. View

Tarallo V, Tudisco L, De Falco S . A placenta growth factor 2 variant acts as dominant negative of vascular endothelial growth factor A by heterodimerization mechanism. Am J Cancer Res. 2011; 1(2):265-274. PMC: 3180054. View

Giri S, Karakoti A, Graham R, Maguire J, Reilly C, Seal S . Nanoceria: a rare-earth nanoparticle as a novel anti-angiogenic therapeutic agent in ovarian cancer. PLoS One. 2013; 8(1):e54578. PMC: 3561344. DOI: 10.1371/journal.pone.0054578. View

10.

Abrahams V, Straszewski S, Kamsteeg M, Hanczaruk B, Schwartz P, Rutherford T . Epithelial ovarian cancer cells secrete functional Fas ligand. Cancer Res. 2003; 63(17):5573-81. View

11.

Diers A, Vayalil P, Oliva C, Griguer C, Darley-Usmar V, Hurst D . Mitochondrial bioenergetics of metastatic breast cancer cells in response to dynamic changes in oxygen tension: effects of HIF-1α. PLoS One. 2013; 8(6):e68348. PMC: 3696014. DOI: 10.1371/journal.pone.0068348. View

12.

Takekawa M, Saito H . A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell. 1998; 95(4):521-30. DOI: 10.1016/s0092-8674(00)81619-0. View

13.

Gatenby R, Gillies R . Why do cancers have high aerobic glycolysis?. Nat Rev Cancer. 2004; 4(11):891-9. DOI: 10.1038/nrc1478. View

14.

Takahashi A, Sasaki H, Kim S, Tobisu K, Kakizoe T, Tsukamoto T . Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 1994; 54(15):4233-7. View

15.

Clark R, Krishnan V, Schoof M, Rodriguez I, Theriault B, Chekmareva M . Milky spots promote ovarian cancer metastatic colonization of peritoneal adipose in experimental models. Am J Pathol. 2013; 183(2):576-91. PMC: 3730760. DOI: 10.1016/j.ajpath.2013.04.023. View

16.

Moiseeva O, Deschenes-Simard X, Pollak M, Ferbeyre G . Metformin, aging and cancer. Aging (Albany NY). 2013; 5(5):330-1. PMC: 3701105. DOI: 10.18632/aging.100556. View

17.

Mu N, Wang Y, Xue F . Metformin: a potential novel endometrial cancer therapy. Int J Gynecol Cancer. 2012; 22(2):181. DOI: 10.1097/IGC.0b013e318233e0e1. View

18.

Menendez J, Joven J, Cufi S, Corominas-Faja B, Oliveras-Ferraros C, Cuyas E . The Warburg effect version 2.0: metabolic reprogramming of cancer stem cells. Cell Cycle. 2013; 12(8):1166-79. PMC: 3674082. DOI: 10.4161/cc.24479. View

19.

Wei S, Liang J, Tsao P, Hsieh F, Yu S, Wong J . Preoperative serum placenta growth factor level is a prognostic biomarker in colorectal cancer. Dis Colon Rectum. 2009; 52(9):1630-6. DOI: 10.1007/DCR.0b013e3181afbdaf. View

20.

Liu J, Li M, Song B, Jia C, Zhang L, Bai X . Metformin inhibits renal cell carcinoma in vitro and in vivo xenograft. Urol Oncol. 2011; 31(2):264-70. DOI: 10.1016/j.urolonc.2011.01.003. View