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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2018 | Research

TNFα induces Ca²⁺ influx to accelerate extrinsic apoptosis in hepatocellular carcinoma cells

Authors: Jianjun Zhu, Mingpeng Jin, Jiaojiao Wang, Hui Zhang, Yousheng Wu, Deyang Li, Xiaoying Ji, Hushan Yang, Chun Yin, Tingting Ren, Jinliang Xing

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Abstract

Background

Tumor necrosis factor-α has been proven an effective anticancer agent in preclinical studies. However, the translation of TNFα from research to clinic has been blocked by significant systemic toxicity and limited efficacy at maximal tolerated dose, which need urgently to be solved.

Methods

The level of cytosolic Ca²⁺ was assessed by Fura-2 in HCC cells. After changing cytosolic Ca²⁺ level by using agonists or inhibitors, cell apoptosis was detected by flow cytometry. We also detected the effect of ionomycin or parvalbumin on the anti-tumor activity of TNFα in a mice model. Lastly, we studied the roles of cytosolic Ca²⁺ in the mitochondrial-dependent intrinsic apoptosis pathway.

Results

Here, we demonstrated that TNFα induced extracellular Ca²⁺ influx into cytoplasm through transient receptor potential channel in HCC cells. Both cytosolic Ca²⁺ scavenger and Ca²⁺-binding protein PV effectively desensitized hepatocellular carcinoma cells to TNFα, whereas combination ionomycin or 1,4,5-inositol triphosphate significantly sensitized HCC cells to TNFα, indicating that the increased level of cytosolic Ca²⁺ was positively correlated with the TNFα-induced cell apoptosis in vitro. In a nude mice xenograft model, our data revealed that TNFα combined with ionomycin remarkably synergized the anti-tumor effect of TNFα. Furthermore, we found that TNFα-mediated extracellular Ca²⁺ influx accelerated TNFα-induced extrinsic apoptosis through activating calpain/IAP/caspase3 pathway.

Conclusions

Our study provides the evidence supporting a novel mechanism by which TNFα induces extracellular Ca²⁺ influx to enhance cell apoptosis and suggests that increasing the level of cytosolic Ca²⁺ might be an alternative strategy to improve the pro-apoptotic activity of TNFα in HCC cells, although suitable chemical or biological reagents need to be further tested.

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Title: TNFα induces Ca2+ influx to accelerate extrinsic apoptosis in hepatocellular carcinoma cells
Authors: Jianjun Zhu
Mingpeng Jin
Jiaojiao Wang
Hui Zhang
Yousheng Wu
Deyang Li
Xiaoying Ji
Hushan Yang
Chun Yin
Tingting Ren
Jinliang Xing
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-018-0714-6

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Abstract

Background

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Conclusions

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