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Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-1R) are mediated by an induction of IGF-1R promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the pancreatic cancer cell line MIA PaCa-2

Oncogene volume 20, pages 8203–8214 (2001)Cite this article

Abstract

In the present study we investigated the mechanisms responsible for and the biological consequences of the constitutive activation of the insulin-like growth factor-1 receptor (IGF-1R) in the MIA PaCa-2 cells. An aberrant increase in the expression and activation of the IGF-1R was observed during the transition of growth states from exponential to quiescent. The increase in IGF-1R expression is preceded by an increase in IGF-1R mRNA transcript and is associated with an increase in the IGF-1R promoter activity. Inhibition of de novo transcription by actinomycin D increased the stability of IGF-1R mRNA in exponentially growing cells, thereby increasing the expression of IGF-1R to a level similar to that seen in quiescent cells. Increased IGF-1R signaling mediated the growth factor independence of quiescent MIA PaCa-2 cells through the constitutive activation of mitogen-activated protein kinase (MAPK). Exogenous IGF-1 increased cell proliferation and activated MAPK and AKT signaling pathways. The resistance of cells to apoptosis by IGF-1R signaling was mediated through MAPK and phosphatidylinositol 3-kinase (PI3K) pathways and a yet unidentified pathway(s). Thus, aberrant regulation of IGF-1R signaling is required for resistance to apoptosis and growth factor independence of MIA PaCa-2 cells. This likely protects cells from unfavorable conditions and allows cells to rapidly re-enter the cell cycle when conditions are favorable.

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Abbreviations

IGF-1:

insulin-like growth factor-1

IGF-1R:

insulin-like growth factor-1 receptor

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

PDGFR:

platelet derived growth factor receptor

TGFα:

transforming growth factor α

IRS-1:

insulin receptor substrate-1

IR:

insulin receptor

IGFBP3:

insulin-like growth factor-1 binding protein-3

MAPK:

mitogen-activated protein kinase

PI3K:

phosphatidylinositol 3-kinase

JAK:

Janus kinase

STAT:

signal transducer and activator of transcription

PARP:

poly-(ADP-ribose) polymerase

STAM2:

signal transduction adaptor molecule

FACS:

fluorescence-activated cell sorter

SFM:

serum-free medium

RNA:

ribonucleic acid

mRNA:

messenger RNA

DNA:

deoxyribonucleic acid

PBS:

phosphate-buffered saline

TBST:

Tris-buffered saline/Tween20

DMEM:

Dulbecco's modified Eagle's medium

EDTA:

ethylene-dichloride tetraacetic acid

SDS-PAGE:

sodium dodecyl sulfate-polyacrylamide gel electrophoresis

RPA:

RNase protection assay

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Acknowledgements

We thank Drs Derek LeRoith (National Institute of Health; Bethesda, Maryland), Charles Roberts (Oregon Health Science University, Portland, Oregon), and Haim Werner (Tel Aviv University; Tel Aviv, Israel) for providing the human IGF-1R receptor plasmids. We also thank Mr Charles Thomas (FACS Laboratory, UTHSCSA) for the FACS analysis.

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Authors and Affiliations

  1. Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, Texas, USA

    Prakash N Nair, Daniel T De Armond, William E Strodel & James W Freeman

  2. Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, Texas, USA

    James W Freeman

  3. Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, Texas, USA

    Martin L Adamo

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  1. Prakash N Nair
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Correspondence to James W Freeman.

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Nair, P., De Armond, D., Adamo, M. et al. Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-1R) are mediated by an induction of IGF-1R promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the pancreatic cancer cell line MIA PaCa-2. Oncogene 20, 8203–8214 (2001). https://doi.org/10.1038/sj.onc.1205044

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