Editors' ChoiceCancer Biology

Eating p62 Is Good for You

Science Signaling  16 Jun 2009:
Vol. 2, Issue 75, pp. ec201
DOI: 10.1126/scisignal.275ec201

Autophagy, a process in which proteins (especially aggregated proteins) and organelles are degraded by the lysosome, operates during starvation to reclaim nutrients and during stress to eliminate damaged cellular constituents. Autophagy has tumor-suppressive effects: Defects in autophagy, such as those caused by allelic loss of beclin1, are frequently detected in human tumors. The protein p62 directs polyubiquitinated or aggregated proteins to the autophagosome through its interaction with Atg (autophagy-related gene) 8. Noting that mice with liver-specific defects in autophagy accumulate p62 aggregates, Mathew et al. (see also Moscat and Diaz-Meco) investigated the role of p62 degradation by autophagy in tumorigenesis. In immortalized baby mouse kidney (iBMK) cells, p62 accumulated after metabolic stress and was eliminated more slowly in autophagy-defective cell lines (which were beclin1+/– or atg5–/–) than in beclin1+/+ cells or atg5+/+ cells. In addition, autophagy-defective cells displayed structural and biochemical evidence of damaged mitochondria when metabolically stressed. Compared with wild-type mice, beclin1+/– mice had more p62 and GRp170 [glucose-related protein 170, an endoplasmic reticulum (ER) chaperone] in lung, heart, and liver tissues and in spontaneous lung and liver tumors, as well as increased activation of the DNA damage response (as assessed by γ-H2AX–positive nuclei) in liver tissue. Because oxidative stress mediated by reactive oxygen species (ROS) can activate the DNA damage response, the authors treated metabolically stressed beclin1+/– or atg5–/– iBMK cells with the ROS scavenger N-acetylcysteine (NAC), which improved cell survival, decreased p62 accumulation, and slowed progression to aneuploidy. Overexpression of p62 tagged with enhanced green fluorescent protein (EGFP) in beclin1+/– or atg5–/– iBMK cells increased ROS concentrations and activation of the DNA damage response compared with beclin1+/+ or atg5+/+ cells. Moreover, tumors caused by p62-EGFP–expressing atg5–/– iBMK cell lines showed increased growth, decreased NF-κB (nuclear factor κB) target gene expression, and greater numbers of γ-H2AX–positive nuclei compared with those caused by atg5–/– iBMK cell lines expressing only EGFP. Thus, defects in autophagy trigger the accumulation of p62, leading to oxidative stress and DNA damage and promoting tumorigenesis.

R. Mathew, C. M. Karp, B. Beaudoin, N. Vuong, G. Chen, H.-Y. Chen, K. Bray, A. Reddy, G. Bhanot, C. Gelinas, R. S. DiPaola, V. Karantza-Wadsworth, E. White, Autophagy suppresses tumorigenesis through elimination of p62. Cell 137, 1062–1075 (2009). [Online Journal]

J. Moscat, M. T. Diaz-Meco, p62 at the crossroads of autophagy, apoptosis, and cancer. Cell 137, 1001–1004 (2009). [Online Journal]