Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival.
Pancreatic endoplasmic reticulum kinase (PERK)-eIF2 alpha signaling, a component of the endoplasmic reticulum (ER) stress response, has been proposed as a therapeutic target due to its importance to cell survival in hypoxic tumors. In this study, we show that in addition to promoting survival, PERK can also suppress tumor growth of advanced carcinomas. Our results show that in squamous carcinoma T-HEp3 cells, which display low PERK-eIF2 alpha signaling, inducible activation of an Fv2E-PERK fusion protein results in a strong G(0)-G(1) arrest in vitro. Most importantly, Fv2E-PERK activation, in addition to promoting survival in vitro, inhibits T-HEp3 and SW620 colon carcinoma growth in vivo. Increased PERK activation is linked to enhanced p-eIF2 alpha levels, translational repression, and a decrease in Ki67, pH 3, and cycD1/D3 levels, but not to changes in angiogenesis or apoptosis. Experimental reduction of PERK activity, or overexpression of GADD34 in a spontaneously arising in vivo quiescent variant of HEp3 cells that displays strong basal PERK-eIF2 alpha activation, reverts their quiescent phenotype. We conclude that the growth-inhibitory function of PERK is preserved in tumors and upon proper reactivation can severely inhibit tumor growth through induction of quiescence. This is an important consideration in the development of PERK-based therapies, as its inhibition may facilitate the proliferation of slow-cycling or dormant tumor cells.
Ranganathan
Aparna C
AC
Department of Biomedical Sciences, School of Public Health, Center for Excellence in Cancer Genomics, University at Albany, State University of New York, Rensselaer, New York, USA.
Ojha
Shishir
S
Kourtidis
Antonis
A
Conklin
Douglas S
DS
Aguirre-Ghiso
Julio A
JA
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002642:Chick Embryo; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D019892:eIF-2 Kinase / Q000235:genetics / Q000502:physiology*
D015852:Eukaryotic Initiation Factor-2; D019892:eIF-2 Kinase