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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

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.

Authors: Yang, Seungwon; Qiang, Lei; Sample, Ashley; Shah, Palak; He, Yu-Ying

Published In J Biol Chem, (2017 02 24)

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 genes HIF-1α, IL-8, BCL-2, and BCL-XL through the accumulation of autophagosomes, p62, and JNK signaling. The activation of NF-κB further increased p62 gene 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.

PubMed ID: 28082672 Exiting the NIEHS site

MeSH Terms: Animals; Antimalarials/pharmacology*; Antineoplastic Agents/pharmacology*; Autophagosomes/drug effects; Autophagosomes/immunology; Autophagy/drug effects; Carcinoma, Squamous Cell/drug therapy; Carcinoma, Squamous Cell/genetics; Carcinoma, Squamous Cell/immunology; Cell Line; Cell Line, Tumor; Chloroquine/pharmacology*; Gene Expression Regulation, Neoplastic/drug effects; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Interleukin-8/genetics; JNK Mitogen-Activated Protein Kinases/immunology*; Melanoma/drug therapy; Melanoma/genetics; Melanoma/immunology; Mice; NF-kappa B/immunology*; Sequestosome-1 Protein/genetics; Sequestosome-1 Protein/immunology*; Signal Transduction/drug effects

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