The anti-cancer drug gefitinib accelerates Fas-mediated apoptosis by enhancing caspase-8 activation in cancer cells
The anti-cancer drug gefitinib accelerates Fas-mediated apoptosis by enhancing caspase-8 activation in cancer cells
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DOI：
10.2131/jts.44.435
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发表时间：
2019-01-01
影响因子：
2
通讯作者：
Matsuzawa, Atsushi
中科院分区：
文献类型：
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作者：
Sekiguchi, Yuto;Yamada, Mayuka;Matsuzawa, Atsushi
Fas/CD 95在T细胞介导的细胞毒作用中起关键作用。越来越多的证据表明，对Fas介导的细胞凋亡的抗性有助于癌细胞逃避免疫破坏，并允许癌细胞增殖和生长。在本研究中，我们发现抗癌药物吉非替尼，一种表皮生长因子受体（EGFR）的酪氨酸激酶抑制剂，具有增强Fas介导的细胞毒性的能力。在非毒性浓度的吉非替尼的存在下，Fas诱导的caspase-8的活化和随后的细胞凋亡显着促进，表明吉非替尼增加Fas介导的细胞凋亡的敏感性。有趣的是，在EGFR或p53敲除（KO）细胞中观察到吉非替尼的作用。这些观察结果表明，EGFR和p53都是增强的原因。另一方面，吉非替尼明显下调热休克蛋白70（HSP 70），如先前报道的。考虑到HSP 70有助于保护细胞免受Fas介导的凋亡，吉非替尼可能通过下调HSP 70来增加对Fas介导的凋亡的敏感性。因此，我们的研究结果揭示了吉非替尼的新特性，这可能为吉非替尼治疗Fas耐药肿瘤的替代治疗方法提供见解。
Fas/CD95 plays a pivotal role in T cell-mediated cytotoxicity. Accumulating evidence has suggested that resistance to Fas-mediated apoptosis contributes to the escape of cancer cells from immune destruction, and allows to undergo proliferation and outgrowth of cancer cells. In this study, we found that the anti-cancer drug gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), has an ability to enhance Fas-mediated cytotoxicity. In the presence of nontoxic concentrations of gefitinib, Fas-induced activation of caspase-8 and subsequent apoptosis was dramatically promoted, suggesting that gefitinib increases the sensitivity to Fas-mediated apoptosis. Interestingly, the effects of gefitinib were observed in EGFR or p53 knockout (KO) cells. These observations indicate that both EGFR and p53 are dispensable for the enhancement. On the other hand, gefitinib clearly downregulated heat shock protein 70 (HSP70) as previously reported. Considering that HSP70 contributes to protection of cells against Fas-mediated apoptosis, gefitinib may increase the sensitivity to Fas-mediated apoptosis by downregulating HSP70. Thus, our findings reveal novel properties of gefitinib, which may provide insight into the alternative therapeutic approaches of gefitinib for Fas-resistant tumors.