Targeting PARP and autophagy evoked synergistic lethality in hepatocellular carcinoma. (6th June 2019)

• Record Type: Journal Article
• Authors: Zai, Wenjing; Chen, Wei; Han, Yuxuan; Wu, Zimei; Fan, Jiajun; Zhang, Xuyao; Luan, Jingyun; Tang, Shijie; Jin, Xin; Fu, Xiang; Gao, Hongjian; Ju, Dianwen; Liu, Hongrui
• Is Part Of: Carcinogenesis. Volume 41:Number 3(2020)
• Page Start: 345
• Page End: 357
• Publication Date: 2019-06-06
• Subjects: Carcinogenesis -- Periodicals; Cancer -- Genetic aspects -- Periodicals; Cancer -- Prevention -- Periodicals; Cancer -- Periodicals; 616.994071
• DOI: 10.1093/carcin/bgz104
• Languages: English
• ISSNs: 0143-3334

Abstract

Abstract: Hepatocellular carcinoma (HCC), one of the most lethal malignancies worldwide, has limited efficient therapeutic options. Here, we first demonstrated that simultaneously targeting poly (ADP-ribose) polymerase (PARP) and autophagy could evoke striking synergistic lethality in HCC cells. Specifically, we found that the PARP inhibitor Niraparib induced cytotoxicity accompanied by significant autophagy formation and autophagic flux in HCC cells. Further experiments showed that Niraparib induced suppression of the Akt/mTOR pathway and activation of the Erk1/2 cascade, two typical signaling pathways related to autophagy. In addition, the accumulation of reactive oxygen species was triggered, which was involved in Niraparib-induced autophagy. Blocking autophagy by chloroquine (CQ) in combination with Niraparib further enhanced cytotoxicity, induced apoptosis and inhibited colony formation in HCC cells. Synergistic inhibition was also observed in Huh7 xenografts in vivo . Mechanistically, we showed that autophagy inhibition abrogated Niraparib-induced cell-cycle arrest and checkpoint activation. Cotreatment with CQ and Niraparib promoted the formation of γ-H2AX foci while inhibiting the recruitment of the homologous recombination repair protein RAD51 to double-strand break sites. Thus, the present study developed a novel promising strategy for the management of HCC in the clinic and highlighted a potential approach to expand the application of PARP inhibitors. Abstract : The research herein demonstrated that inhibiting PARP could distinctly stimulate autophagy and autophagy flux in HCC cells, combinational inhibiting PARP and autophagy could evoke synergistic lethality both in vitro and in vivo .