Insulin-like growth factor-I protects cells from ER stress-induced apoptosis via enhancement of the adaptive capacity of endoplasmic reticulum

R. Novosyadlyy, N. Kurshan, D. Lann, A. Vijayakumar, Shoshana Yakar, D. LeRoith

Research output: Contribution to journalArticle

Abstract

Disruption of endoplasmic reticulum (ER) homeostasis causes accumulation of unfolded and misfolded proteins in the ER, triggering the ER stress response, which can eventually lead to apoptosis when ER dysfunction is severe or prolonged. Here we demonstrate that human MCF-7 breast cancer cells, as well as murine NIH/3T3 fibroblasts, are rescued from ER stress-initiated apoptosis by insulin-like growth factor-I (IGF-I). IGF-I significantly augments the adaptive capacity of the ER by enhancing compensatory mechanisms such as the IRE1α-, PERK- and ATF6-mediated arms of ER stress signalling. During ER stress, IGF-I stimulates translational recovery and induces expression of the key molecular chaperone protein Grp78/BiP, thereby enhancing the folding capacity of the ER and promoting recovery from ER stress. We also demonstrate that the antiapoptotic activity of IGF-I during ER stress may be mediated by a novel, as yet unidentified, signalling pathway(s). Application of signal transduction inhibitors of MEK (U1026), PI3K (LY294002 and wortmannin), JNK (SP600125), p38 (SB203580), protein kinases A and C (H-89 and staurosporine) and STAT3 (Stattic) does not prevent IGF-I-mediated protection from ER stress-induced apoptosis. Taken together, these data demonstrate that IGF-I protects against ER stress-induced apoptosis by increasing adaptive mechanisms through enhancement of ER stress-signalling pathways, thereby restoring ER homeostasis and preventing apoptosis.

Original languageEnglish (US)
Pages (from-to)1304-1317
Number of pages14
JournalCell Death and Differentiation
Volume15
Issue number8
DOIs
StatePublished - Aug 2008

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Endoplasmic Reticulum Stress
Insulin-Like Growth Factor I
Endoplasmic Reticulum
Apoptosis
Homeostasis
Protein Unfolding
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Molecular Chaperones
Staurosporine
Mitogen-Activated Protein Kinase Kinases
p38 Mitogen-Activated Protein Kinases
Cyclic AMP-Dependent Protein Kinases
Phosphatidylinositol 3-Kinases
Protein Kinase C
Signal Transduction
Fibroblasts
Breast Neoplasms

ASJC Scopus subject areas

  • Cell Biology

Cite this

Insulin-like growth factor-I protects cells from ER stress-induced apoptosis via enhancement of the adaptive capacity of endoplasmic reticulum. / Novosyadlyy, R.; Kurshan, N.; Lann, D.; Vijayakumar, A.; Yakar, Shoshana; LeRoith, D.

In: Cell Death and Differentiation, Vol. 15, No. 8, 08.2008, p. 1304-1317.

Research output: Contribution to journalArticle

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