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Roflumilast enhances cisplatin-sensitivity and reverses cisplatin-resistance of ovarian cancer cells via cAMP/PKA/CREB-FtMt signalling axis.
Cell Prolif. 2018 Oct; 51(5):e12474.CP

Abstract

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

OVCAR3 and SKOV3 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 OVCAR3 and SKOV3 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 SKOV3 or SKOV3-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.

Authors+Show Affiliations

Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.Department of Gynecology, People's Hospital of Huadu District, Guangzhou, China.Department of Obstetrics and Gynecology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30069985

Citation

Gong, Shipeng, et al. "Roflumilast Enhances Cisplatin-sensitivity and Reverses Cisplatin-resistance of Ovarian Cancer Cells Via cAMP/PKA/CREB-FtMt Signalling Axis." Cell Proliferation, vol. 51, no. 5, 2018, pp. e12474.
Gong S, Chen Y, Meng F, et al. Roflumilast enhances cisplatin-sensitivity and reverses cisplatin-resistance of ovarian cancer cells via cAMP/PKA/CREB-FtMt signalling axis. Cell Prolif. 2018;51(5):e12474.
Gong, S., Chen, Y., Meng, F., Zhang, Y., Li, C., Zhang, G., Huan, W., & Wu, F. (2018). Roflumilast enhances cisplatin-sensitivity and reverses cisplatin-resistance of ovarian cancer cells via cAMP/PKA/CREB-FtMt signalling axis. Cell Proliferation, 51(5), e12474. https://doi.org/10.1111/cpr.12474
Gong S, et al. Roflumilast Enhances Cisplatin-sensitivity and Reverses Cisplatin-resistance of Ovarian Cancer Cells Via cAMP/PKA/CREB-FtMt Signalling Axis. Cell Prolif. 2018;51(5):e12474. PubMed PMID: 30069985.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Roflumilast enhances cisplatin-sensitivity and reverses cisplatin-resistance of ovarian cancer cells via cAMP/PKA/CREB-FtMt signalling axis. AU - Gong,Shipeng, AU - Chen,Yongning, AU - Meng,Fanliang, AU - Zhang,Yadi, AU - Li,Chanyuan, AU - Zhang,Guangping, AU - Huan,Wu, AU - Wu,Fei, Y1 - 2018/08/02/ PY - 2017/12/26/received PY - 2018/03/30/accepted PY - 2018/8/3/pubmed PY - 2018/10/3/medline PY - 2018/8/3/entrez SP - e12474 EP - e12474 JF - Cell proliferation JO - Cell Prolif VL - 51 IS - 5 N2 - 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: OVCAR3 and SKOV3 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 OVCAR3 and SKOV3 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 SKOV3 or SKOV3-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. SN - 1365-2184 UR - https://www.unboundmedicine.com/medline/citation/30069985/Roflumilast_enhances_cisplatin_sensitivity_and_reverses_cisplatin_resistance_of_ovarian_cancer_cells_via_cAMP/PKA/CREB_FtMt_signalling_axis_ L2 - https://doi.org/10.1111/cpr.12474 DB - PRIME DP - Unbound Medicine ER -