Abstract 5755: PR/AMPK-IGF/PI3K network plays a major role on progestin-resistance in endometrial cancer therapy
Authors: Chao Gu, Weiwei Shan, Yiling Lu, Yinhua Yu, Xiaojun Chen
Journal: Cancer Research (2012)

Abstract Progestin-resistance is a main obstacle to the success of conservative therapy in type I young endometrial cancer patients. We have established a progestin-resistant endometrial cancer cell line by long-term induction with gradual increasing of progestin concentration. Our previous study confirmed that progestin activated PI3K/Akt pathway through a non-genomic pathway independent of Progesterone receptor (PR). Blocking PI3K pathway up-regulated PR expression and restored the anti-proliferative effect of medoxyprogesterone acetate (MPA) in progestin-resistant cells. We propose that PI3K/Akt activation may not be the only mechanism of progestin-resistance. To further explore other molecular events leading to progestin-resistance and to search for any possible approaches to reverse this resistance in endometrial cancer, we have characterized functional proteomics by reverse phase protein array (RPPA) in progestin-sensitive and -resistant endometrial cancer cells, and the RPPA results were confirmed by Western blots. Our results demonstrated up-regulation of Insulin-like growth factor-1 receptor (IGF-1R), and down-regulation of IGF binding protein 2 (IGFBP2) and Ataxia Telangiectasia (ATM) [an upstream molecule of adenosine monophosphate-activated kinase (AMPK) pathway] in progestin-resistant cells, suggesting that IGF/AMPK metabolic pathways are involved in progestin-resistance of endometrial cancer therapy. We further identified the differential effects of insulin stimulation on metabolic changes in progestin-sensitive and -resistant cell lines. We found that acute stimulation with high concentration of insulin not only activated PI3K/Akt, but also reduced the expression of PR, EGFR and IGF-1R, and further mediated proliferation of primary endometrial cancer cells. Continually stimulation with insulin reduced MPA-mediated anti-proliferation effect in progestin-sensitive cells, but no effect in progestin-resistant cells, indicating the existing of altered insulin-responsiveness in progestin-resistant cells. Furthermore, Metformin, an insulin-independent AMPK activator and is commonly used as an insulin sensitizer, could restore progestin sensitivity in progestin-resistant endometrial cancer cells. The restoration was demonstrated directly related to the inhibition of PI3K/Akt pathway, activation of AMPK and upregulation of PR transcription. In summary, our study revealed that PR/AMPK-IGF/PI3K network plays an important role on progestin-resistance in endometrial cancer therapy. The combinatory treatment of progestin with PI3K inhibitor, or with AMPK activator-metformin might be an effective conservative approach for endometrial cancer patients who developed progestin-resistance in their therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5755. doi:1538-7445.AM2012-5755