Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival

Aparna R Sertil, Shishir Ojha, Antonis Kourtidis, Douglas S. Conklin, Julio A. Aguirre-Ghiso

Research output: Contribution to journalArticle

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Abstract

Pancreatic endoplasmic reticulum kinase (PERK)-eIF2α 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-eIF2α signaling, inducible activation of an Fv2E-PERK fusion protein results in a strong G 0-G1 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-eIF2α 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-eIF2α 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.

Original languageEnglish (US)
Pages (from-to)3260-3268
Number of pages9
JournalCancer Research
Volume68
Issue number9
DOIs
StatePublished - May 1 2008
Externally publishedYes

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Endoplasmic Reticulum
Phosphotransferases
Growth
Neoplasms
Carcinoma
Endoplasmic Reticulum Stress
Protein Kinases
Squamous Cell Carcinoma
Cell Survival
Colon
Apoptosis
Phenotype
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival. / Sertil, Aparna R; Ojha, Shishir; Kourtidis, Antonis; Conklin, Douglas S.; Aguirre-Ghiso, Julio A.

In: Cancer Research, Vol. 68, No. 9, 01.05.2008, p. 3260-3268.

Research output: Contribution to journalArticle

Sertil, Aparna R ; Ojha, Shishir ; Kourtidis, Antonis ; Conklin, Douglas S. ; Aguirre-Ghiso, Julio A. / Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival. In: Cancer Research. 2008 ; Vol. 68, No. 9. pp. 3260-3268.
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