Inhibiting the PI3K/Akt pathway reversed progestin resistance in endometrial cancer

• Published in: Cancer science 2011-03, Vol.102 (3), p.557-564
• Main Authors: Gu, Chao, Zhang, Zhenbo, Yu, Yinhua, Liu, Yingtao, Zhao, Fengdi, Yin, Lianhua, Feng, Youji, Chen, Xiaojun
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Hormonal - pharmacology; Biological and medical sciences; Cell Line, Tumor; Chromones - pharmacology; Drug Resistance, Neoplasm; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - pathology; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Medroxyprogesterone Acetate - pharmacology; Mice; Mice, Inbred BALB C; Morpholines - pharmacology; Original; Phosphatidylinositol 3-Kinases - physiology; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - physiology; Receptors, Progesterone - analysis; Receptors, Progesterone - physiology; Signal Transduction - drug effects; Tumors
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/j.1349-7006.2010.01829.x

Progestin resistance is the main obstacle to successful conservative therapy in young endometrial cancer patients. To investigate the molecular events that lead to progestin resistance and to find a possible way to reverse progestin resistance in endometrial cancer, we established a progestin‐resistant Ishikawa cell line by long‐term progestin treatment to downregulate progesterone receptor (PR) expression. Both medoxyprogesterone acetate (MPA) and LY294002, a phosphatidylinositol 3‐kinase (PI3K) inhibitor, were assayed for their effects on the proliferation of progestin‐sensitive and progestin‐resistant cancer cells, respectively. The MPA inhibited the PI3K/Akt pathway and suppressed cell proliferation in progestin‐sensitive Ishikawa cells, but activated the PI3K/Akt pathway and had no effect on cell proliferation in progestin‐resistant Ishikawa cells or HEC‐1A cells. Inhibiting the PI3K/Akt pathway by LY294002 upregulated PR expression and diminished cell growth, especially in progestin‐resistant endometrial cancer cells. In vivo endometrial cancer xenograft studies in nude mice also showed that inhibiting the PI3K/Akt pathway reversed progestin resistance in endometrial cancer. Our results indicate that activation of the PI3K/Akt pathway by progestin without PR mediation plays an important role in progestin resistance to endometrial cancer cells. In addition, inhibiting the PI3K/Akt pathway might reverse progestin resistance in endometrial cancer. (Cancer Sci 2011; 102: 557–564)