title: Inhibition of AKT sensitizes chemoresistant ovarian cancer cells to cisplatin by abrogating S and G2/M arrest.
abstract: The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is frequently altered in human malignancies and Akt over-expression and/or activation induces malignant transformation and chemoresistance. However, the role of Akt in the mechanisms of chemoresistance remains elusive. Here we reported that cisplatin treatment of chemosensitive, but not resistant, ovarian cancer cells (OVCAs) markedly increased the cell proportion in sub-G1 phase. Cisplatin however caused a significant accumulation of the resistant cells in S and G2/M phases, which was associated with a rapid and sustained checkpoint kinase 1 (Chk1) activation. In contrast, while cisplatin also elicited a rapid activation of Chk1 in sensitive cells, it markedly decreased total ChK1 and phospho-Chk1 contents over 12 h. Over-expression of dominant negative (DN)-AKT alone increased phospho-Chk1 content, and induced G2/M arrest and apoptosis. However, it inhibited Chk1 activation and G2/M arrest with combination of cisplatin treatment, resulting in p53-independent apoptosis. Furthermore, the responses of the chemoresistant cells to cisplatin were attenuated with forced expression of constitutive active AKT2. Chk1 knock-down also facilitated cisplatin-induced apoptosis in chemoresistant cells. Our studies implicate that, in addition to its cell survival and anti-apoptotic actions, Akt might also play an important role in the regulation of G2-M transition, possibly via up-regulation of Chk1 activity and stability. These data provide strong support for the concept that Akt is important in cell cycle regulation in the control of chemosensitivity in OVCAs and offers an alternate regulatory pathway for the development of rationale therapy for cisplatin-resistant ovarian cancer.
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China.
authors.forename: Hai-Lan
authors.initials: HL
authors.lastname: Piao
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, and Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Canada; Department of Cellular and Molecular Medicine, and Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Canada; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Qing
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China.
authors.forename: Da-Jin
authors.initials: DJ
authors.lastname: Li
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China; Department of Obstetrics and Gynecology, and Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Canada. Electronic address: mrdu@fudan.edu.cn.
authors.forename: Mei-Rong
authors.initials: MR
authors.lastname: Du
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and the Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau; Department of Obstetrics and Gynecology, and Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Canada; Department of Cellular and Molecular Medicine, and Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Canada; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada. Electronic address: btsang@ohri.ca.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Tsang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000071877:Checkpoint Kinase 1 / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D000071877:Checkpoint Kinase 1; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin
keywords: Chemoresistance; Cisplatin; Ovarian cancer cells; PI3K/Akt