Radiation-induced autophagy promotes esophageal squamous cell carcinoma cell survival via the LKB1 pathway.
Radiotherapy is an important treatment modality for esophageal cancer; however, the clinical efficacy of radiotherapy is limited by tumor radioresistance. In the present study, we explored the hypothesis that radiation induces tumor cell autophagy as a cytoprotective adaptive response, which depends on liver kinase B1 (LKB1) also known as serine/threonine kinase 11 (STK11). Radiation-induced Eca-109 cell autophagy was found to be dependent on signaling through the LKB1 pathway, and autophagy inhibitors that disrupted radiation-induced Eca-109 cell autophagy increased cell cycle arrest and cell death in vitro. Inhibition of autophagy also reduced the clonogenic survival of the Eca-109 cells. When treated with radiation alone, human esophageal carcinoma xenografts showed increased LC3B and p-LKB1 expression, which was decreased by the autophagy inhibitor chloroquine. In vivo inhibition of autophagy disrupted tumor growth and increased tumor apoptosis when combined with 6 Gy of ionizing radiation. In summary, our findings elucidate a novel mechanism of resistance to radiotherapy in which radiation-induced autophagy, via the LKB1 pathway, promotes tumor cell survival. This indicates that inhibition of autophagy can serve as an adjuvant treatment to improve the curative effect of radiotherapy.
Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430014, P.R. China.
Chi
C
Lu
Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430014, P.R. China.
Conghua
C
Xie
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects*; D002294:Carcinoma, Squamous Cell / Q000532:radiotherapy*; D059447:Cell Cycle Checkpoints / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D002738:Chloroquine / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000532:radiotherapy*; D000077277:Esophageal Squamous Cell Carcinoma; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; D002738:Chloroquine; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases