PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage.
To proliferate and expand in an environment with limited nutrients, cancer cells co-opt cellular regulatory pathways that facilitate adaptation and thereby maintain tumor growth and survival potential. The endoplasmic reticulum (ER) is uniquely positioned to sense nutrient deprivation stress and subsequently engage signaling pathways that promote adaptive strategies. As such, components of the ER stress-signaling pathway represent potential antineoplastic targets. However, recent investigations into the role of the ER resident protein kinase, RNA-dependent protein kinase (PKR)-like ER kinase (PERK) have paradoxically suggested both pro- and anti-tumorigenic properties. We have used animal models of mammary carcinoma to interrogate the contribution of PERK in the neoplastic process. The ablation of PERK in tumor cells resulted in impaired regeneration of intracellular antioxidants and accumulation of reactive oxygen species triggering oxidative DNA damage. Ultimately, PERK deficiency impeded progression through the cell cycle because of the activation of the DNA damage checkpoint. Our data reveal that PERK-dependent signaling is used during both tumor initiation and expansion to maintain redox homeostasis, thereby facilitating tumor growth.
Bobrovnikova-Marjon
E
E
The Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Grigoriadou
C
C
Pytel
D
D
Zhang
F
F
Ye
J
J
Koumenis
C
C
Cavener
D
D
Diehl
J A
JA
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D055029:Inverted Repeat Sequences; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009928:Organ Specificity; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D014758:Viral Core Proteins / Q000235:genetics; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D000957:Antigens, Viral, Tumor; D051267:NF-E2-Related Factor 2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014758:Viral Core Proteins; D019892:eIF-2 Kinase; C055976:p27 antigen, Mouse mammary tumor virus
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