MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy
MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy
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DOI：
10.4161/auto.20268
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发表时间：
2012-07-01
期刊：
影响因子：
13.3
通讯作者：
Gongora, Celine
中科院分区：
文献类型：
--
作者：
Paillas, Salome;Causse, Annick;Gongora, Celine
最近，我们发现丝裂原活化蛋白激酶（MAPK）MAPK 14/p38 α参与结肠癌细胞对喜树碱相关药物的耐药性。在此，我们进一步研究了涉及这种耐药性的细胞机制，并表明在其中TP 53被基因消融的HCT 116人结直肠腺癌细胞（HCT 116-TP 53 KO）中，组成型活性MAPK 14/p38 a的过表达降低了细胞对SN-38（伊立替康的活性代谢物）的敏感性，抑制了细胞增殖并诱导了存活自噬。由于已知自噬促进癌细胞对化疗和放射治疗的抗性，因此我们研究了MAPK 14/p38 α、自噬和对伊立替康的抗性之间的关系。我们证明SN 38诱导自噬依赖于MAPK 14/p38 α激活。最后，我们发现MAPK 14/p38 α或自噬的抑制均使HCT 116-TP 53 KO细胞对药物治疗敏感。我们的数据证明这两种效应是相互关联的，因为自噬在耐药性中的作用需要MAPK 14/p38 α。我们的研究结果强调了对喜树碱相关药物耐药的新机制的存在：在SN 38诱导后，MAPK 14/p38 α被激活并触发促进生存的自噬，以保护肿瘤细胞免受药物的细胞毒性作用。因此，结肠癌细胞可以通过抑制MAPK 14/p38或自噬而对药物治疗敏感。
Recently we have shown that the mitogen-activated protein kinase (MAPK) MAPK14/p38 alpha is involved in resistance of colon cancer cells to camptothecin-related drugs. Here we further investigated the cellular mechanisms involved in such drug resistance and showed that, in HCT116 human colorectal adenocarcinoma cells in which TP53 was genetically ablated (HCT116-TP53KO), overexpression of constitutively active MAPK14/p38a decreases cell sensitivity to SN-38 (the active metabolite of irinotecan), inhibits cell proliferation and induces survival-autophagy. Since autophagy is known to facilitate cancer cell resistance to chemotherapy and radiation treatment, we then investigated the relationship between MAPK14/p38 alpha, autophagy and resistance to irinotecan. We demonstrated that induction of autophagy by SN38 is dependent on MAPK14/p38 alpha activation. Finally, we showed that inhibition of MAPK14/p38 alpha or autophagy both sensitizes HCT116-TP53KO cells to drug therapy. Our data proved that the two effects are interrelated, since the role of autophagy in drug resistance required the MAPK14/p38 alpha. Our results highlight the existence of a new mechanism of resistance to camptothecin-related drugs: upon SN38 induction, MAPK14/p38 alpha is activated and triggers survival-promoting autophagy to protect tumor cells against the cytotoxic effects of the drug. Colon cancer cells could thus be sensitized to drug therapy by inhibiting either MAPK14/p38 or autophagy.