TNFAIP8 promotes prostate cancer cell survival by inducing autophagy

// Suryakant Niture 1, 2 , Malathi Ramalinga 2 , Habib Kedir 1, 2 , Dorrelyn Patacsil 2 , Samiksha S. Niture 3 , James Li 4 , Haresh Mani 5 , Simeng Suy 4 , Sean Collins 4 and Deepak Kumar 1, 2, 4 1 Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, 27707 NC, USA 2 Cancer Research Laboratory, University of the District of Columbia, Washington, 20008 DC, USA 3 Catonsville High School, Catonsville, 21228 MD, USA 4 Lombardi Comprehensive Cancer Center, Georgetown University, Washington, 20008 DC, USA 5 Department of Pathology, Inova Fairfax Hospital, Falls Church, 22042 VA, USA Correspondence to: Deepak Kumar, email: dkumar@nccu.edu Keywords: TNFAIP8; autophagy; cell survival; prostate cancer; neuroendocrine differentiation Received: March 14, 2018      Accepted: May 03, 2018      Published: June 01, 2018 ABSTRACT Tumor necrosis factor-α-inducible protein 8 (TNFAIP8) is a TNF-α inducible anti-apoptotic protein with multiple roles in tumor growth and survival. Mechanisms of cell survival by TNFAIP8 remain elusive. We investigated the role of TNFAIP8 in the regulation of the cell cycle, autophagy, cell survival and neuroendocrine differentiation in prostate cancer cells. We showed that TNFAIP8 dysregulates cell-cycle-related proteins, in PC3 cells. Oncogenic cell survival, drug resistance and dysregulation of cell cycle-related proteins are often associated with autophagy. We demonstrated that TNFAIP8 induces autophagy by increasing expression of autophagy effectors such as LC3β I/II, Beclin1, 4EBP1, p62, and SIRT1. We also demonstrated that TNFAIP8 interacts with autophagy-related protein 3 (ATG3). TNFα treatment increased the expression of TNFAIP8, which was associated with increased autophagy and decreased apoptosis. We also observed an increase in expression of neuroendocrine differentiation markers, synaptophysin and chromogranin A, and drug resistance to anticancer drugs, docetaxel and doxorubicin, in cells transfected with TNFAIP8. Collectively, our findings reveal that by the creation of cellular autophagy events, TNFAIP8 promotes cell survival and drug resistance in prostate cancer cells.