Open AccessRoflumilast enhances cisplatin‐sensitivity and reverses cisplatin‐resistance of ovarian cancer cells via cAMP / PKA / CREB ‐FtMt signalling axis
Author(s) -
Gong Shipeng,
Chen Yongning,
Meng Fanliang,
Zhang Yadi,
Li Chanyuan,
Zhang Guangping,
Huan Wu,
Wu Fei
Publication year - 2018
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/cpr.12474
Subject(s) - creb , roflumilast , cancer research , apoptosis , downregulation and upregulation , cisplatin , cell growth , ovarian cancer , chemistry , phosphorylation , biology , cancer , microbiology and biotechnology , medicine , biochemistry , chemotherapy , transcription factor , copd , gene
Objective We previously demonstrated the roflumilast inhibited cell proliferation and increased cell apoptosis in ovarian cancer. In this study, we aimed to investigate the roles of roflumilast in development of cisplatin ( DDP )‐sensitive and ‐resistant ovarian cancer. Methods OVCAR 3 and SKOV 3 were selected and the corresponding DDP ‐resistant cells were constructed. Cell viability, proliferation, apoptosis, cycle were performed. Expression cAMP , PKA , CREB , phosphorylation of CREB and FtMt were detected. The roles of roflumilast in development of DDP ‐sensitive and ‐resistant ovarian cancer were confirmed by xenograft model. Results Roflumilast + DDP inhibited cell proliferation, and induced cell apoptosis and G0/G1 arrest in OVCAR 3 and SKOV 3 cells, roflumilast induced expression of FtMt, the activity of cAMP and PKA and phosphorylation of CREB in ovarian cancer cells and the above‐effect were inhibited by H89. Downregulation of CREB inhibited the roflumilast‐increased DDP sensitivity of ovarian cancer cells, and the roflumilast‐induced FtMt expression and phosphorylation of CREB . Also, roflumilast reversed cisplatin‐resistance, and induced expression of FtMt and activation of cAMP / PKA / CREB in DDP ‐resistant ovarian cancer cells. Similarly, treated with H89 or downregulation of CREB inhibited the changes induced by roflumilast. In vivo, roflumilast inhibited the development of SKOV 3 or SKOV 3‐ DDP ‐R xenograft models. Conclusions Roflumilast enhanced DDP sensitivity and reversed the DDP resistance of ovarian cancer cells via activation of cAMP / PKA / CREB pathway and upregulation of the downstream FtMt expression, which has great promise in clinical treatment.