PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage

Abstract

In order 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 anti-neoplastic targets. However, recent investigations into the role of the ER resident protein kinase PERK have paradoxically suggested both pro- and anti-tumorigenic properties. We have utilized animal models of mammary carcinoma to interrogate PERK contribution 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 due to the activation of the DNA damage checkpoint. Our data reveal that PERK-dependent signaling is utilized during both tumor initiation and expansion to maintain redox homeostasis and thereby facilitates tumor growth.

Rôle de l’heme regulated inhibitor(HRI) dans la résistance à l’apoptose

“…Les expériences de déplétion par des siARN ont révélé un rôle potentiel de la protéine PKR dans le développement tumoral via la résistance des cellules cancéreuses au traitement anticancéreux, ainsi que leur prolifération [37][38][39]. De même, l'inactivation de PERK, par des approches génétique [40] ou pharmacologique [41], induit une surproduction des ROS induisant des dommages oxydants de l'ADN ; ceux-ci provoquent l'activation des points de contrôle du cycle cellulaire, inhibant ainsi la prolifération des cellules cancéreuses in vitro et ralentissant la croissance tumorale in vivo. Ces résultats montrent un rôle protumoral de PERK et suggèrent aussi une fonction protectrice potentielle de cette kinase contre des agents chimiothérapeutiques qui fonctionnent via la génération des ROS.…”

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

“…Inactivation of the PERK pathway by either generating mutations in the kinase domain of PERK or introducing a phosphorylation-resistant form of eIF2a impairs cell survival under extreme hypoxia [83]. Furthermore, PERK limits oxidative DNA damage through Nrf2 activation which further promotes cancer cell proliferation and survival [84]. The involvement of UPR in cancer is currently promising therapeutic target for the treatment of cancer [85].…”

Generation and characterization of an analog-sensitive PERK allele

“…8,10 Among these is the primary UPR effector PERK, which has been characterized for its role in tumor growth, cell migration, metastasis, angiogenesis, survival of ECM-detached cells, and the epithelialmesenchymal transition. [11][12][13][14][15][16][17] In light of these pro-tumorigenic effects, there has been significant interest in developing cancer therapeutics that target PERK activity, and in defining the molecular mechanisms that underlie PERK function. 18,19 To further interrogate PERK-signaling networks, we have generated an analog-sensitive PERK allele that specifically binds N 6 -alkylated ATP analogs.…”