title: Inhibiting the PI3K/Akt pathway reversed progestin resistance in endometrial cancer.
abstract: 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.
authors.affiliation: Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Gu
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Yu
authors.forename: Yingtao
authors.initials: Y
authors.lastname: Liu
authors.forename: Fengdi
authors.initials: F
authors.lastname: Zhao
authors.forename: Lianhua
authors.initials: L
authors.lastname: Yin
authors.forename: Youji
authors.initials: Y
authors.lastname: Feng
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology; D011980:Receptors, Progesterone / Q000032:analysis / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D002867:Chromones; D017258:Medroxyprogesterone Acetate; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011980:Receptors, Progesterone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one