Roflumilast restores cAMP/PKA/CREB signaling axis for FtMt-mediated tumor inhibition of ovarian cancer
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Shipeng Gong1,*, Yongning Chen1,*, Fanliang Meng1, Yadi Zhang1, Huan Wu2 and Fei Wu1
1Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
2Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing University of Medical Sciences, Chongqing 400010, P.R. China
*These authors contributed equally to the study and should be considered as co-first authors
Shipeng Gong, email: [email protected]
Keywords: roflumilast; cAMP; CREB; FtMt; ovarian cancer
Received: August 02, 2017 Accepted: November 13, 2017 Published: December 02, 2017
The abrogation of cAMP generation by overexpression of PDE isoforms promotes the inflammatory pathology, and the PDE inhibitors have showed the potential anti-inflammation effects in clinical. However, the function of PDE inhibitors in cancer treatment remains unclear. We here investigated the role of PDE4 inhibitor Roflumilast in the treatment of ovarian cancer. We found that Roflumilast could effectively inhibit the proliferation, and induce apoptosis and cell cycle arrest in two ovarian cancer cell lines OVCAR3 and SKOV3. Meanwhile, the cAMP/PKA/CREB signals was activated by Roflumilast, which was accompanied by the up-regulation of mitochondrial ferritin (FtMt) level. Interestingly, forced expression of FtMt in ovarian cancer enhanced the apoptosis and inhibited tumor growth and the PKA inhibitor H89 and knockdown of CREB significantly repressed the expression of FtMt to restore the tumor proliferation and inhibit apoptosis. In addition, we found that Roflumilast-induced phosphorylated CREB directly promoted transcription of FtMt, indicating that Roflumilast up-regulated the expression of FtMt in ovarian cancer via cAMP/PKA/CREB signals. The anti-tumor role of Roflumilast in vivo was also demonstrated, the treatment of roflumilast effectively inhibited tumor proliferation and elevated the FtMt expression to restrict the tumor growth via the activation of cAMP/PKA/CREB signals in ovarian cancer.
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