MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy MAPK14/p38α induces survival autophagy

• Published in: Autophagy Vol. 8; no. 7; pp. 1098 - 112
• Main Authors: Paillas, Salome, Causse, Annick, Marzi, Laetitia, de Médina, Philippe, Poirot, Marc, Denis, Vincent, Vezzio-Vie, Nadia, Espert, Lucile, Arzouk, Hayat, Coquelle, Arnaud, Martineau, Pierre, del Rio, Maguy, Pattingre, Sophie, Gongora, Céline
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 01.07.2012
• Subjects: Cancer; Cellular Biology; Life Sciences; MAPK14/p38. Survival Autophagy. Irinotecan resistance. Colon cancer. Chemotherapy
• ISSN: 1554-8627; 1554-8635
• DOI: 10.4161/auto.20268

Recently we have shown that the mitogen-activated protein kinase (MAPK) MAPK14/p38α 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/p38α 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/p38α, autophagy and resistance to irinotecan. We demonstrated that induction of autophagy by SN38 is dependent on MAPK14/p38α activation. Finally, we showed that inhibition of MAPK14/p38α 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/p38α. Our results highlight the existence of a new mechanism of resistance to camptothecin-related drugs: upon SN38 induction, MAPK14/p38α 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.