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

Salome Paillas (1) , Annick Causse (1) , Laetitia Marzi (1) , Philippe de Médina (2) , Marc Poirot (2) , Vincent Denis (1) , Nadia Vezzio-Vie (1) , Lucile Espert (3) , Hayat Arzouk (1) , Arnaud Coquelle (1) , Pierre Martineau (1) , Maguy del Rio (1) , Sophie Pattingre (1) , Céline Gongora (1)

1 IRCM - U896 Inserm - UM1 - Institut de recherche en cancérologie de Montpellier
2 INSERM U563 - CNRS UMR1037 - Centre de Physiopathologie de Toulouse-Purpan
3 IRIM - Institut de Recherche en Infectiologie de Montpellier

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.

Mots clés: MAPK14/p38. Survival Autophagy. Irinotecan resistance. Colon cancer. Chemotherapy.; MAPK14/p38. Survival Autophagy. Irinotecan resistance. Colon cancer. Chemotherapy

Domaines: Biologie cellulaire; Cancer

Salome Paillas, Annick Causse, Laetitia Marzi, Philippe de Médina, Marc Poirot, et al.. MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy.: MAPK14/p38α induces survival autophagy. Autophagy, 2012, 8 (7), pp.1098-112. ⟨10.4161/auto.20268⟩. ⟨inserm-00705786⟩