title: NF-κB Signaling Activation Induced by Chloroquine Requires Autophagosome, p62 Protein, and c-Jun N-terminal Kinase (JNK) Signaling and Promotes Tumor Cell Resistance.
abstract: Macroautophagy (hereafter autophagy) is a catabolic cellular self-eating process by which unwanted organelles or proteins are delivered to lysosomes for degradation through autophagosomes. Although the role of autophagy in cancer has been shown to be context-dependent, the role of autophagy in tumor cell survival has attracted great interest in targeting autophagy for cancer therapy. One family of potential autophagy blockers is the quinoline-derived antimalarial family, including chloroquine (CQ). However, the molecular basis for tumor cell response to CQ remains poorly understood. We show here that in both squamous cell carcinoma cells and melanoma tumor cells, CQ induced NF-κB activation and the expression of its target genesHIF-1α,IL-8, BCL-2,andBCL-XLthrough the accumulation of autophagosomes, p62, and JNK signaling. The activation of NF-κB further increasedp62gene expression. Either genetic knockdown of p62 or inhibition of NF-κB sensitized tumor cells to CQ, resulting in increased apoptotic cell death following treatment. Our findings provide new molecular insights into the CQ response in tumor cells and CQ resistance in cancer therapy. These findings may facilitate development of improved therapeutic strategies by targeting the p62/NF-κB pathway.
authors.affiliation: Department of Medicine, Section of Dermatology.
authors.forename: Seungwon
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Medicine, Section of Dermatology.
authors.forename: Lei
authors.initials: L
authors.lastname: Qiang
authors.affiliation: Department of Medicine, Section of Dermatology; Committee on Cancer Biology, University of Chicago, Chicago, Illinois 60637.
authors.forename: Ashley
authors.initials: A
authors.lastname: Sample
authors.affiliation: Department of Medicine, Section of Dermatology.
authors.forename: Palak
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Medicine, Section of Dermatology; Committee on Cancer Biology, University of Chicago, Chicago, Illinois 60637. Electronic address: yyhe@medicine.bsd.uchicago.edu.
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: He
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000071182:Autophagosomes / Q000187:drug effects / Q000276:immunology; D001343:Autophagy / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000276:immunology*; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D016328:NF-kappa B; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D002738:Chloroquine; D048031:JNK Mitogen-Activated Protein Kinases
keywords: NF-κB; autophagy; chloroquine; melanoma; p62 (sequestosome 1(SQSTM1)); tumor cell biology