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. 2021 Oct 1:282:119762.
doi: 10.1016/j.lfs.2021.119762. Epub 2021 Jun 26.

The HSP90 inhibitor, XL888, enhanced cell apoptosis via downregulating STAT3 after insufficient radiofrequency ablation in hepatocellular carcinoma

Chen Sun  1 , Ming Bai  2 , Weiwei Ke  1 , Xiaoxun Wang  3 , Xiangxuan Zhao  4 , Zaiming Lu  5
Affiliations
Free article

The HSP90 inhibitor, XL888, enhanced cell apoptosis via downregulating STAT3 after insufficient radiofrequency ablation in hepatocellular carcinoma

Chen Sun et al. Life Sci. .
Free article

Abstract

Aims: Radiofrequency ablation (RFA) is the first-line option for early-stage hepatocellular carcinoma (HCC). However, the residual tumor attributed to insufficient RFA (iRFA) led to tumor recurrence and metastasis. Novel combination strategies are urgently needed to enhance efficiency of RFA.

Main methods: For in vitro iRFA models, HCC cells were placed in a water bath at 46 °C for 10 min and then returned to the original incubator. For in vivo models, HCC cells were implanted subcutaneously into nude mice. The nude mice were then randomly assigned into 4 groups: control group, XL888 group, iRFA group, combination of XL888 and iRFA group. CCK8 was performed to detect cell viability; Hoechst 33258 was used to explore nuclear morphology; The expression levels of proteins were demonstrated by western blotting; Co-localization of HSP90 and STAT3 was elucidated by immunofluorescence confocal microscopy; Immunohistochemistry was used to explore expression levels of proteins at tissue level.

Key findings: XL888 promoted apoptosis of HCC cells induced by heat via inhibiting expression levels of Mcl-1 and cleaved-caspase 3 in vivo and in vitro. XL888 attenuated the complex formation of HSP90 and STAT3, leading to decreased expression levels of STAT3 and p-STAT3. In human HCC tissues, IHC scores of HSP90 were positively correlated with those of STAT3. Overexpression of STAT3 rescued cell apoptosis induced by co-treatment of XL888 and heat.

Significance: We implied that XL888 promoted apoptosis of HCC cells induced by heat via disrupting the binding of HSP90 and STAT3, providing theoretical basis for a novel combination strategy for HCC.

Keywords: Apoptosis; HSP90; Hepatocellular carcinoma; Insufficient RFA; STAT3; XL888.

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