Autophagy Suppresses Tumorigenesis through Elimination of p62

Robin Mathew, Cristina M. Karp, Brian Beaudoin, Nhan Vuong, Guanghua Chen, Hsin Yi Chen, Kevin Bray, Anupama Reddy, Gyan Bhanot, Celine Gelinas, Robert S. DiPaola, Vassiliki Karantza-Wadsworth, Eileen White

Research output: Contribution to journalArticlepeer-review

1447 Scopus citations


Allelic loss of the essential autophagy gene beclin1 occurs in human cancers and renders mice tumor-prone suggesting that autophagy is a tumor-suppression mechanism. While tumor cells utilize autophagy to survive metabolic stress, autophagy also mitigates the resulting cellular damage that may limit tumorigenesis. In response to stress, autophagy-defective tumor cells preferentially accumulated p62/SQSTM1 (p62), endoplasmic reticulum (ER) chaperones, damaged mitochondria, reactive oxygen species (ROS), and genome damage. Moreover, suppressing ROS or p62 accumulation prevented damage resulting from autophagy defects indicating that failure to regulate p62 caused oxidative stress. Importantly, sustained p62 expression resulting from autophagy defects was sufficient to alter NF-κB regulation and gene expression and to promote tumorigenesis. Thus, defective autophagy is a mechanism for p62 upregulation commonly observed in human tumors that contributes directly to tumorigenesis likely by perturbing the signal transduction adaptor function of p62-controlling pathways critical for oncogenesis.

Original languageEnglish
Pages (from-to)1062-1075
Number of pages14
Issue number6
StatePublished - Jun 12 2009

Bibliographical note

Funding Information:
We thank Drs. Heintz, Yue, and Jin for providing beclin1 +/+ and beclin1 +/− mice, Dr. Mizushima for providing atg5 +/+ and atg5 −/− mice, Dr. Zimmermann for GRp170 antibody and Dr. Moscat for myc-p62 and p62-EGFP plasmids. This work was supported by grants from the National Institutes of Health (R37 CA53370 and RO1 CA130893) to E.W., (K99CA133181) to V.K.W., and Department of Defense (W81XWH06-1-0514 and W81XWH05) to E.W. and R.S.D.



ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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