Autophagy suppresses tumorigenesis through elimination of p62.
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-kappaB 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.
Mathew
Robin
R
University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Karp
Cristina M
CM
Beaudoin
Brian
B
Vuong
Nhan
N
Chen
Guanghua
G
Chen
Hsin-Yi
HY
Bray
Kevin
K
Reddy
Anupama
A
Bhanot
Gyan
G
Gelinas
Celine
C
Dipaola
Robert S
RS
Karantza-Wadsworth
Vassiliki
V
White
Eileen
E
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D051758:Transcription Factor TFIIH; D014157:Transcription Factors
D048868:Adaptor Proteins, Signal Transducing; C490981:Gtf2h1 protein, mouse; D018832:Molecular Chaperones; D016328:NF-kappa B; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; D019704:Protein Disulfide-Isomerases