UMMS Affiliation

Department of Cancer Biology and the Cancer Center

Publication Date

8-3-2005

Document Type

Article

Subjects

Adaptor Proteins, Signal Transducing; Adenocarcinoma; Animals; Antigens, CD29; Cell Adhesion; Cell Growth Processes; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphoproteins; Prostatic Neoplasms; Receptor, IGF Type 1; inhibitors

Disciplines

Cancer Biology | Endocrinology, Diabetes, and Metabolism

Abstract

The cells' ability to proliferate in response to growth factor stimulation is significantly altered during cancer progression. To investigate the mechanisms underlying these alterations in prostate cancer, the role and expression of beta1A integrin and type 1 insulin-like growth factor receptor (IGF-IR), known to contribute to cell proliferation and transformation, were analyzed. Using small interfering RNA oligonucleotides to down-regulate beta1A, we show that beta1A expression is required for IGF-IR-mediated prostate cancer cell proliferation and anchorage-independent growth. In vivo, using age-matched transgenic adenocarcinoma of mouse prostate (TRAMP) mice at different stages of prostate cancer [prostatic intraepithelial neoplasia, PIN; well-differentiated adenocarcinoma, WD; and poorly differentiated adenocarcinoma, PD], the expression of beta1A and of IGF-IR was studied. beta1A and IGF-IR expression levels were concurrently up-regulated in high PIN and WD, whereas their expression did not correlate in late-stage PD. In contrast to the up-regulated expression of beta1A, the levels of beta1C, a beta1 cytoplasmic variant that inhibits cell proliferation, were down-regulated in all stages of prostate cancer. A similar expression pattern was observed for a beta1C downstream effector, Grb2-associated binder-1 (Gab1) which is known to inhibit IGF-IR phosphorylation. To analyze in vitro the mechanistic implications of beta1A, beta1C, and Gab1 deregulation in prostate cancer, we investigated whether expression of either beta1 variant in beta1-null cells affected IGF-IR localization. We found that IGF-IR and beta1A were colocalized in highly specialized integrin signaling compartments, designated focal contacts. However, in the presence of beta1C, IGF-IR remained diffuse on the cell surface and did not localize to focal contacts. The findings that beta1 integrins and IGF-IR are concurrently deregulated and that expression of beta1 integrins is necessary to achieve appropriate IGF-IR intracellular distribution point to the important role that the cross-talk between these receptors may have during prostate cancer progression and will be helpful in formulating new therapeutic strategies.

Rights and Permissions

Citation: Cancer Res. 2005 Aug 1;65(15):6692-700. Link to article on publisher's site

DOI of Published Version

10.1158/0008-5472.CAN-04-4315

Related Resources

Link to article in PubMed

Journal/Book/Conference Title

Cancer research

PubMed ID

16061650

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