title: Geldanamycin, an inhibitor of Hsp90, increases paclitaxel-mediated toxicity in ovarian cancer cells through sustained activation of the p38/H2AX axis.
abstract: Paclitaxel is a mitotic inhibitor used in ovarian cancer chemotherapy. Unfortunately, due to the rapid genetic and epigenetic changes in adaptation to stress induced by anticancer drugs, cancer cells are often able to become resistant to single or multiple anticancer agents. However, it remains largely unknown how paclitaxel resistance happens. In this study, we generated a cell line of acquired resistance to paclitaxel therapy, A2780T, which is cross-resistant to other antimitotic drugs, such as PLK1 inhibitor or AURKA inhibitor. Immunoblotting revealed significant alterations in cell-cycle-related and apoptotic-related proteins involved in key signaling pathways. In particular, phosphorylation of p38, which activates H2AX, was significantly decreased in A2780T cells compared to the parental A2780 cells. Geldanamycin (GA), an inhibitor of Hsp90, sustained activation of the p38/H2AX axis, and A2780T cells were shown to be more sensitive to GA compared to A2780 cells. Furthermore, treatment of A2780 and A2780T cells with GA significantly enhanced sensitivity to paclitaxel. Meanwhile, GA cooperated with paclitaxel to suppress tumor growth in a mouse ovarian cancer xenograft model. In conclusion, GA may sensitize a subset of ovarian cancer to paclitaxel, particularly those tumors in which resistance is driven by inactivation of p38/H2AX axis.
authors.affiliation: Cancer Biology Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Mo
authors.affiliation: Cancer Biology Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cancer Biology Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Cancer Biology Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Cancer Biology Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Cancer Biology Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Hao
authors.affiliation: Cancer Biology Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China. qingleigao@hotmail.com.
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Cancer Biology Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China. supercpb520@163.com.
authors.forename: Pingbo
authors.initials: P
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; C468783:H2AX protein, human; D018841:HSP90 Heat-Shock Proteins; D006657:Histones; D047029:Lactams, Macrocyclic; D048051:p38 Mitogen-Activated Protein Kinases; D017239:Paclitaxel; C001277:geldanamycin
keywords: Geldanamycin; Hsp90 inhibitor; Ovarian cancer; Paclitaxel; p38/H2AX axis