Roflumilast restores cAMP/PKA/CREB signaling axis for FtMt-mediated tumor inhibition of ovarian cancer.

Shipeng Gong,Fanliang Meng,Huan Wu,Fei Wu,Yadi Zhang,Yongning Chen

doi:10.18632/oncotarget.22866

Abstract

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.

Highlights

As the most lethal gynecologic cancer, ovarian cancer is the leading cause of gynecologic cancer death in developed countries, with an incidence of 6.1 cases per 100.000 women, a rate of mortality of 4.3 deaths per 100.000 women [1, 2]
The Cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cyclic AMP response element-binding protein (CREB) signals was activated by Roflumilast, which was accompanied by the up-regulation of mitochondrial ferritin (FtMt) level
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

Summary

Introduction

As the most lethal gynecologic cancer, ovarian cancer is the leading cause of gynecologic cancer death in developed countries, with an incidence of 6.1 cases per 100.000 women, a rate of mortality of 4.3 deaths per 100.000 women [1, 2]. Aberrant expression of PDE induces the imbalance of cAMP levels in the majority of inflammatory cells to promote the several inflammatory disorders, such as chronic obstructive pulmonary disease (COPD) or active psoriatic arthritis [6, 7]. The PDE inhibitors, such as PDE4 inhibitor Roflumilast, are effective anti-inflammatory agents to reactivate the cAMP signals inflammatory processes [6, 8]. The function of PDE inhibitors and cAMP signals is elusive during the carcinogenesis. Et al found that PDE4 inhibitor roflumilast and prednisone could restore the cyclic-AMP-mediated growth suppression in B-cell tumors via the inhibition of PI3K/ AKT activity [12]. We speculated that PDE inhibitor was the potential strategy for the treatment of ovarian cancer via regulation of cAMP signals

Methods

Results

Conclusion