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Gefitinib enhances human colon cancer cells to TRAIL-induced apoptosis of via autophagy- and JNK-mediated death receptors upregulation

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Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell-specific apoptosis-inducing cytokine with little toxicity to most normal cells. Here, we report that gefitinib and TRAIL in combination produce a potent synergistic effect on TRAIL-sensitive human colon cancer HCT116 cells and an additive effect on TRAIL-resistant HT-29 cells. Interestingly, gefitinib increases the expression of cell surface receptors DR4 and DR5, possibly explaining the synergistic effect. Knockdown of DR4 and DR5 by siRNA significantly decreases gefitinib- and TRAIL-mediated cell apoptosis, supporting this idea. Because the inhibition of gefitinib-induced autophagy by 3-MA significantly decreases DR4 and DR5 upregulation, as well as reduces gefitinib- and TRAIL-induced apoptosis, we conclude that death receptor upregulation is autophagy mediated. Furthermore, our results indicate that death receptor expression may also be regulated by JNK activation, because pre-treatment of cells with JNK inhibitor SP600125 significantly decreases gefitinib-induced death receptor upregulation. Interestingly, SP600125 also inhibits the expression CHOP, yet CHOP has no impact on death receptor expressions. We also find here that phosphorylation of Akt and ERK might also be required for TRAIL sensitization. In summary, our results indicate that gefitinib effectively enhances TRAIL-induced apoptosis, likely via autophagy and JNK- mediated death receptor expression and phosphorylation of Akt and ERK.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81302172) and the China Postdoctoral Science Foundation (2013M530959 & 2014T70270). We would also like to thank Prof. KH Mayo for critical reading and editing of this manuscript.

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Authors and Affiliations

  1. Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun, 130024, China

    Lei Chen, Yue Meng, Xiaoqing Guo, Xiaotong Sheng, Guihua Tai, Hairong Cheng & Yifa Zhou

  2. Department of Radiology, The Second Part of the First Hospital, Jilin University, 3302 Jilin Road, Changchun, 130024, China

    Fenglei Zhang

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  1. Lei Chen
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  2. Yue Meng
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Correspondence to Hairong Cheng or Yifa Zhou.

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Chen, L., Meng, Y., Guo, X. et al. Gefitinib enhances human colon cancer cells to TRAIL-induced apoptosis of via autophagy- and JNK-mediated death receptors upregulation. Apoptosis 21, 1291–1301 (2016). https://doi.org/10.1007/s10495-016-1287-5

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