Prostate cancer (PCa) is one of the most common cancers in men. Patients with recurrent disease initially respond to androgen-deprivation therapy, but the tumor eventually progresses into castration-resistant PCa. Thus, new therapeutic approaches for PCa resistance to current treatments are urgently needed. Here, we report that cardiac glycoside neriifolin suppresses the malignancy of cancer cells via increasing DNA damage and apoptosis through activation of endoplasmic reticulum stress (ERS) in prostate cancers. We found that cardiac glycoside neriifolin markedly inhibited the cell growth and induced apoptosis in prostate cancer cells. Transcriptome sequence analysis revealed that neriifolin significantly induced DNA damage and double strand breaks (DSBs), validated with attenuation expression of genes in DSBs repair and increasing phosphorylated histone H2AX (γ-H2AX) foci formation, a quantitative marker of DSBs. Moreover, we found that neriifolin also activated ERS, evidenced by upregulation and activation of ERS related proteins, including eukaryotic initiation factor 2α (eIF2α), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and C/EBP homologous protein (CHOP) as well as downregulation of CCAATenhancerbinding protein alpha (C/EBP-α), a transcriptional factor that forms heterodimers with CHOP. In addition, neriifolin treatment dramatically inhibited the by tumor growth, which were reversed by CHOP loss or overexpression of C/EBP-α in nude mice. Mechanistically, neriifolin suppressed the tumor growth by increasing DNA damage and apoptosis through CHOP-C/EBP-α signaling axis of ERS in prostate cancers. Taken together, these results suggest that cardiac glycoside neriifolin may be a potential tumor-specific chemotherapeutic agent in prostate cancer treatment.
Keywords: Apoptosis; Cardiac glycoside; DNA damage repair; Endoplasmic reticulum stress; Neriifolin; Prostate cancer.
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