Niture Suryakant, Ramalinga Malathi, Kedir Habib, Patacsil Dorrelyn, Niture Samiksha S, Li James, Mani Haresh, Suy Simeng, Collins Sean, Kumar Deepak
Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, 27707 NC, USA.
Cancer Research Laboratory, University of the District of Columbia, Washington, 20008 DC, USA.
Oncotarget. 2018 Jun 1;9(42):26884-26899. doi: 10.18632/oncotarget.25529.
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.
肿瘤坏死因子-α诱导蛋白8（TNFAIP8）是一种肿瘤坏死因子-α诱导的抗凋亡蛋白，在肿瘤生长和存活中具有多种作用。TNFAIP8介导细胞存活的机制仍不清楚。我们研究了TNFAIP8在前列腺癌细胞的细胞周期调控、自噬、细胞存活和神经内分泌分化中的作用。我们发现，在PC3细胞中，TNFAIP8会使细胞周期相关蛋白失调。致癌性细胞存活、耐药性以及细胞周期相关蛋白的失调通常与自噬有关。我们证明，TNFAIP8通过增加自噬效应分子如LC3β I/II、Beclin1、4EBP1、p62和SIRT1的表达来诱导自噬。我们还证明，TNFAIP8与自噬相关蛋白3（ATG3）相互作用。肿瘤坏死因子α处理可增加TNFAIP8的表达，这与自噬增加和凋亡减少有关。我们还观察到，在转染TNFAIP8的细胞中，神经内分泌分化标志物突触素和嗜铬粒蛋白A的表达增加，并且对多西他赛和阿霉素等抗癌药物产生耐药性。总的来说，我们的研究结果表明，通过引发细胞自噬事件，TNFAIP8可促进前列腺癌细胞的存活和耐药性。
