Leptin stimulates ovarian cancer cell growth and inhibits apoptosis by increasing cyclin D1 and Mcl-1 expression via the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways Corrigendum in /10.3892/ijo.2016.3564

Chen,Chiachen; Chang,Yuan-Ching; Lan,Michael   S.; Breslin,Mary

doi:10.3892/ijo.2013.1789

Leptin stimulates ovarian cancer cell growth and inhibits apoptosis by increasing cyclin D1 and Mcl-1 expression via the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways

Corrigendum in: /10.3892/ijo.2016.3564

Authors:
- Chiachen Chen
- Yuan-Ching Chang
- Michael S. Lan
- Mary Breslin
View Affiliations

Affiliations: Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan, R.O.C., Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan, R.O.C., Research Institute for Children, Children's Hospital, New Orleans, LA, USA
Published online on: January 23, 2013 https://doi.org/10.3892/ijo.2013.1789
Pages: 1113-1119

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Obesity is known to be an important risk factor for many types of cancer, such as breast, prostate, liver and endometrial cancer. Recently, epidemiological studies have indicated that obesity correlates with an increased risk of developing ovarian cancer, the most lethal gynecological cancer in developed countries. Leptin is predominantly produced by adipocytes and acts as a growth factor and serum leptin levels positively correlate with the amount of body fat. In this study, we investigated the effects of leptin on the growth of ovarian cancer cells and the underlying mechanism(s) of action. Our results showed that leptin stimulated the growth of the OVCAR-3 ovarian cancer cell line using MTT assay and trypan blue exclusion. Using western blot analysis, we found that leptin enhanced the expression of cyclin D1 and Mcl-1, which are important regulators of cell proliferation and the inhibition of apoptosis. To investigate the signaling pathways that mediate the effects of leptin, cells were treated with leptin plus specific inhibitors of JAK2, PI3K̸Akt and MEK/ERK1/2 and analysis of the phosphorylation state of proteins was carried out by western blot assays. We showed that the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways were involved in the growth-stimulating effect of leptin on ovarian cancer cell growth and the specific inhibitors of PI3K/Akt and MEK/ERK1/2 revealed that these two pathways interacted with each other. Our data demonstrate that leptin upregulates the expression of cyclin D1 and Mcl-1 to stimulate cell growth by activating the PI3K/Akt and MEK/ERK1/2 pathways in ovarian cancer.

View Figures

View References

1	Beehler GP, Sekhon M, Baker JA, Teter BE, McCann SE, Rodabaugh KJ and Moysich KB: Risk of ovarian cancer associated with BMI varies by menopausal status. J Nutr. 136:2881–2886. 2006.PubMed/NCBI
2	Olsen CM, Green AC, Whiteman DC, Sadeghi S, Kolahdooz F and Webb PM: Obesity and the risk of epithelial ovarian cancer: a systematic review and meta-analysis. Eur J Cancer. 43:690–709. 2007. View Article : Google Scholar : PubMed/NCBI
3	Ioka A, Tsukuma H, Ajiki W and Oshima A: Ovarian cancer incidence and survival by histologic type in Osaka, Japan. Cancer Sci. 94:292–296. 2003. View Article : Google Scholar : PubMed/NCBI
4	Bray GA: The underlying basis for obesity: relationship to cancer. J Nutr. 132:3451S–3455S. 2002.PubMed/NCBI
5	Leitzmann MF, Koebnick C, Danforth KN, Brinton LA, Moore SC, Hollenbeck AR, Schatzkin A and Lacey JV Jr: Body mass index and risk of ovarian cancer. Cancer. 115:812–822. 2009. View Article : Google Scholar : PubMed/NCBI
6	Schouten LJ, Rivera C, Hunter DJ, Spiegelman D, Adami HO, Arslan A, Beeson WL, van den Brandt PA, Buring JE, Folsom AR, Fraser GE, Freudenheim JL, Goldbohm RA, Hankinson SE, Lacey JV Jr, Leitzmann M, Lukanova A, Marshall JR, Miller AB, Patel AV, Rodriguez C, Rohan TE, Ross JA, Wolk A, Zhang SM and Smith-Warner SA: Height, body mass index, and ovarian cancer: a pooled analysis of 12 cohort studies. Cancer Epidemiol Biomarkers Prev. 17:902–912. 2008. View Article : Google Scholar : PubMed/NCBI
7	Calle EE, Rodriguez C, Walker-Thurmond K and Thun MJ: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 348:1625–1638. 2003. View Article : Google Scholar : PubMed/NCBI
8	Rodriguez C, Jacobs EJ, Patel AV, Calle EE, Feigelson HS, Fakhrabadi-Shokoohi D and Thun MJ: Jewish ethnicity and prostate cancer mortality in two large US cohorts. Cancer Causes Control. 13:271–277. 2002. View Article : Google Scholar : PubMed/NCBI
9	Pavelka JC, Brown RS, Karlan BY, Cass I, Leuchter RS, Lagasse LD and Li AJ: Effect of obesity on survival in epithelial ovarian cancer. Cancer. 107:1520–1524. 2006. View Article : Google Scholar : PubMed/NCBI
10	Key T, Appleby P, Barnes I and Reeves G; Endogenous Hormones and Breast Cancer Collaborative Group: Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst. 94:606–616. 2002. View Article : Google Scholar : PubMed/NCBI
11	Risch HA: Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst. 90:1774–1786. 1998. View Article : Google Scholar : PubMed/NCBI
12	Hu X, Juneja SC, Maihle NJ and Cleary MP: Leptin - a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst. 94:1704–1711. 2002. View Article : Google Scholar
13	Chen C, Chang YC, Liu CL, Chang KJ and Guo IC: Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1. Breast Cancer Res Treat. 98:121–132. 2006. View Article : Google Scholar : PubMed/NCBI
14	Sharma D, Saxena NK, Vertino PM and Anania FA: Leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal-transduction pathways. Endocr Relat Cancer. 13:629–640. 2006. View Article : Google Scholar
15	Somasundar P, Frankenberry KA, Skinner H, Vedula G, McFadden DW, Riggs D, Jackson B, Vangilder R, Hileman SM and Vona-Davis LC: Prostate cancer cell proliferation is influenced by leptin. J Surg Res. 118:71–82. 2004. View Article : Google Scholar : PubMed/NCBI
16	Uddin S, Bu R, Ahmed M, Abubaker J, Al-Dayel F, Bavi P and Al-Kuraya KS: Overexpression of leptin receptor predicts an unfavorable outcome in Middle Eastern ovarian cancer. Mol Cancer. 8:742009. View Article : Google Scholar : PubMed/NCBI
17	Garofalo C and Surmacz E: Leptin and cancer. J Cell Physiol. 207:12–22. 2006. View Article : Google Scholar
18	Chen C, Chang YC, Liu CL, Liu TP, Chang KJ and Guo IC: Leptin induces proliferation and anti-apoptosis in human hepatocarcinoma cells by up-regulating cyclin D1 and down-regulating Bax via a Janus kinase 2-linked pathway. Endocr Relat Cancer. 14:513–529. 2007. View Article : Google Scholar : PubMed/NCBI
19	Choi JH, Park SH, Leung PC and Choi KC: Expression of leptin receptors and potential effects of leptin on the cell growth and activation of mitogen-activated protein kinases in ovarian cancer cells. J Clin Endocrinol Metab. 90:207–210. 2005. View Article : Google Scholar : PubMed/NCBI
20	Buettner R, Mora LB and Jove R: Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 8:945–954. 2002.PubMed/NCBI
21	Heiser D, Labi V, Erlacher M and Villunger A: The Bcl-2 protein family and its role in the development of neoplastic disease. Exp Gerontol. 39:1125–1135. 2004. View Article : Google Scholar : PubMed/NCBI
22	Reynolds JE, Yang T, Qian L, Jenkinson JD, Zhou P, Eastman A and Craig RW: Mcl-1, a member of the Bcl-2 family, delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells. Cancer Res. 54:6348–6352. 1994.PubMed/NCBI
23	Michels J, Johnson PW and Packham G: Mcl-1. Int J Biochem Cell Biol. 37:267–271. 2005. View Article : Google Scholar
24	Shigemasa K, Katoh O, Shiroyama Y, Mihara S, Mukai K, Nagai N and Ohama K: Increased MCL-1 expression is associated with poor prognosis in ovarian carcinomas. Jpn J Cancer Res. 93:542–550. 2002. View Article : Google Scholar : PubMed/NCBI
25	Kuo ML, Chuang SE, Lin MT and Yang SY: The involvement of PI 3-K/Akt-dependent up-regulation of Mcl-1 in the prevention of apoptosis of Hep3B cells by interleukin-6. Oncogene. 20:677–685. 2001. View Article : Google Scholar : PubMed/NCBI
26	Leu CM, Chang C and Hu C: Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway. Oncogene. 19:1665–1675. 2000. View Article : Google Scholar : PubMed/NCBI
27	Wei LH, Kuo ML, Chen CA, Chou CH, Cheng WF, Chang MC, Su JL and Hsieh CY: The anti-apoptotic role of interleukin-6 in human cervical cancer is mediated by up-regulation of Mcl-1 through a PI 3-K/Akt pathway. Oncogene. 20:5799–5809. 2001. View Article : Google Scholar : PubMed/NCBI
28	Rouet-Benzineb P, Aparicio T, Guilmeau S, Pouzet C, Descatoire V, Buyse M and Bado A: Leptin counteracts sodium butyrate-induced apoptosis in human colon cancer HT-29 cells via NF-κB signaling. J Biol Chem. 279:16495–16502. 2004.PubMed/NCBI
29	Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, et al: Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 376:37–43. 1995. View Article : Google Scholar : PubMed/NCBI
30	Germain M, Affar EB, D’Amours D, Dixit VM, Salvesen GS and Poirier GG: Cleavage of automodified poly(ADP-ribose) polymerase during apoptosis. Evidence for involvement of caspase-7. J Biol Chem. 274:28379–28384. 1999. View Article : Google Scholar : PubMed/NCBI
31	Knudsen KE, Diehl JA, Haiman CA and Knudsen ES: Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene. 25:1620–1628. 2006. View Article : Google Scholar : PubMed/NCBI
32	Wang JM, Chao JR, Chen W, Kuo ML, Yen JJ and Yang-Yen HF: The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB. Mol Cell Biol. 19:6195–6206. 1999.PubMed/NCBI
33	Ogden CL, Carroll MD, Kit BK and Flegal KM: Prevalence of obesity in the United States, 2009–2010. NCHS Data Brief. 1–8. 2012.
34	Flegal KM, Carroll MD, Kit BK and Ogden CL: Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA. 307:491–497. 2012.
35	Bray GA: Drug treatment of obesity. Rev Endocr Metab Disord. 2:403–418. 2001. View Article : Google Scholar
36	Simonin K, Brotin E, Dufort S, Dutoit S, Goux D, N’Diaye M, Denoyelle C, Gauduchon P and Poulain L: Mcl-1 is an important determinant of the apoptotic response to the BH3-mimetic molecule HA14-1 in cisplatin-resistant ovarian carcinoma cells. Mol Cancer Ther. 8:3162–3170. 2009. View Article : Google Scholar : PubMed/NCBI
37	Varin E, Denoyelle C, Brotin E, Meryet-Figuière M, Giffard F, Abeilard E, Goux D, Gauduchon P, Icard P and Poulain L: Downregulation of Bcl-xL and Mcl-1 is sufficient to induce cell death in mesothelioma cells highly refractory to conventional chemotherapy. Carcinogenesis. 31:984–993. 2010. View Article : Google Scholar : PubMed/NCBI
38	Brotin E, Meryet-Figuière M, Simonin K, Duval RE, Villedieu M, Leroy-Dudal J, Saison-Behmoaras E, Gauduchon P, Denoyelle C and Poulain L: Bcl-XL and MCL-1 constitute pertinent targets in ovarian carcinoma and their concomitant inhibition is sufficient to induce apoptosis. Int J Cancer. 126:885–895. 2010.PubMed/NCBI
39	Weng C, Li Y, Xu D, Shi Y and Tang H: Specific cleavage of Mcl-1 by caspase-3 in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in Jurkat leukemia T cells. J Biol Chem. 280:10491–10500. 2005. View Article : Google Scholar : PubMed/NCBI