RMP/URI inhibits both intrinsic and extrinsic apoptosis through different signaling pathways.

Abstract:

:The evading apoptosis of tumor cells may result in chemotherapy resistance. Therefore, investigating what molecular events contribute to drug-induced apoptosis, and how tumors evade apoptotic death, provides a paradigm to explain the relationship between cancer genetics and treatment sensitivity. In this study, we focused on the role of RMP/URI both in cisplatin-induced endogenous apoptosis and in TRAIL-induced exogenous apoptosis in HCC cells. Although flow cytometric analysis indicated that RMP overexpression reduced the apoptosis rate of HCC cells treated with both cisplatin and TRAIL, there was a difference in mechanism between the two treatments. Western blot showed that in intrinsic apoptosis induced by cisplatin, the overexpression of RMP promoted the Bcl-xl expression both in vitro and in vivo. Besides, RMP activated NF-κB/p65(rel) through the phosphorylation of ATM. However, in TRAIL-induced extrinsic apoptosis, RMP significantly suppressed the transcription and expression of P53. Moreover, the forced expression of P53 could offset this inhibitory effect. In conclusion, we presumed that RMP inhibited both intrinsic and extrinsic apoptosis through different signaling pathways. NF-κB was distinctively involved in the RMP circumvention of intrinsic apoptosis, but not in the extrinsic apoptosis of HCC cells. RMP might play an important role in defects of apoptosis, hence the chemotherapeutic resistance in hepatocellular carcinoma. These studies are promising to shed light on a more rational approach to clinical anticancer drug design and therapy.

journal_name

Int J Biol Sci

authors

Ji Y,Shen J,Li M,Zhu X,Wang Y,Ding J,Jiang S,Chen L,Wei W

doi

10.7150/ijbs.36829

subject

Has Abstract

pub_date

2019-10-15 00:00:00

pages

2692-2706

issue

12

issn

1449-2288

pii

ijbsv15p2692

journal_volume

15

pub_type

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