MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy.
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.
Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.
Salome
S
Paillas
Annick
A
Causse
Laetitia
L
Marzi
Philippe
P
de Medina
Marc
M
Poirot
Vincent
V
Denis
Nadia
N
Vezzio-Vie
Lucile
L
Espert
Hayat
H
Arzouk
Arnaud
A
Coquelle
Pierre
P
Martineau
Maguy
M
Del Rio
Sophie
S
Pattingre
Céline
C
Gongora
D001343:Autophagy / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D055786:Gene Knockout Techniques; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; D048308:Mitogen-Activated Protein Kinase 14; D002166:Camptothecin