Metformin down-regulates endometrial carcinoma cell secretion of IGF-1 and expression of IGF-1R.

Yu Zhang,Zheng Zeng,Xiao-Mao Li,Huan Wang,Meng-Xiong Li

doi:10.7314/apjcp.2015.16.1.221

Abstract

As metformin can inhibit endometrial carcinoma (EC) cell growth and the insulin growth factor (IGF) system is active in EC, the question of whether t can regulate endometrial carcinoma cell secretion of IGF-1 or expression of IGF-1 receptor (IGF-1R) is of interest. In this study, serum IGF-1 levels in EC patients were found to be comparable with that in the non EC patients (p>0.05). However, the IGF-1 level in the medium of cultured cells after treatment with metformin was decreased (p<0.05). IGF-1R was highly expressed in human endometrial carcinoma paraffin sections, but IGF-1R and phosphor-protein kinase B/protein kinase B (p-Akt/ Akt) expression was down-regulated after metformin treatment (p<0.05). In summary, metformin can reduce the secretion of IGF-1 by Ishikawa and JEC EC cell lines and their expression of IGF-1R to deactivate downstream signaling involving the PI-3K/Akt pathway to inhibit endometrial carcinoma cell growth.

Highlights

Endometrial cancer is a most common gynecologic malignant tumor and the fourth malignant tumor for women in developed country (Barakat et al, 2007)
Endometrial carcinoma cells can synthesize and secrete insulin growth factor (IGF)-I and IGF-II, which can integrate with their IGF-1 receptor (IGF-1R) membrane receptor system and thereby cause continuous proliferation of tumor cells (Pavelic et al, 2007)
The concentration of IGF-1 measured was lower in the group treated with 10mM of metformin than that in control group with the cancer development, progress and prognosis (Creighton et al, 2008; Torng et al, 2008), but some studies show no change (Lukanov et al, 2008; Lacey et al, 2004; Weiderpass et al, 2003) or decrease (Gunter et al, 2008) of serum IGF-1 level in endometrial carcinoma cases

Summary

Introduction

Endometrial cancer is a most common gynecologic malignant tumor and the fourth malignant tumor for women in developed country (Barakat et al, 2007). Growth factors are polypeptides that act by autocrine, paracrine, and endocrine pathways to regulate cell proliferation and death (Goustin et al, 1986; Liang K et al, 2014). The major players in extracellular signal are growth factor receptors. The type-1 insulin-like growth factor receptor (IGF-1R) is one member of tyrosine protein kinase receptor family, which is important for the establishment of a malignant cell phenotype, cell metastasis, protection from apoptosis and enhancement of cell proliferation (Baserga, 1995; Morrison et al, 2002; Samani et al, 2004). Levels of IGF-1R have been correlated with tumor progression through phosphatidylinositol-3-kinase/ protein kinase B/the mammalian target of Rapamycin, PI-3K/Akt/mTOR and rat sarcoma/ rapidly accelerated fibrosarcoma/extracellular regulated protein kinases (Ras/Raf/Erk) signaling pathways (Casamassima et al, 1998; Sachdev et al, 2004). Endometrial carcinoma cells can synthesize and secrete IGF-I and IGF-II, which can integrate with their IGF-1R membrane receptor system and thereby cause continuous proliferation of tumor cells (Pavelic et al, 2007)

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Conclusion