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J Urol. 2007 Jul;178(1):292-300. Epub 2007 May 17.

Targeting beta2-microglobulin mediated signaling as a novel therapeutic approach for human renal cell carcinoma.

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  • 1Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Abstract

PURPOSE:

We previously reported that the biological functions of beta2-microglobulin include antigen presentation and oncogenic activity. In the current study we investigated the direct role of beta2-microglobulin in the regulation of human renal cell carcinoma cell growth and the possible apoptotic inducing effect of blocking the beta2-microglobulin signaling pathway using an anti-beta2-microglobulin neutralizing antibody.

MATERIALS AND METHODS:

We examined the effects of recombinant beta2-microglobulin protein and anti-beta2-microglobulin antibody on renal cell carcinoma cell growth and apoptosis in vitro. To seek a molecular understanding of anti-beta2-microglobulin antibody induced apoptosis we analyzed alterations in the growth and survival signaling components in the phosphatidylinositol 3-kinase/Akt, extracellular signal-regulated kinase and c-jun N-terminal kinase mediated pathways using corresponding kinase inhibitors in SN12C cells.

RESULTS:

Recombinant beta2-microglobulin protein increased the growth of the 3 human renal cell carcinoma cell lines SN12C, Caki-1 and ACHN in a dose and time dependent manner. Treatment of SN12C, Caki-1 and ACHN cells with an anti-beta2-microglobulin polyclonal antibody strongly suppressed the growth of these cells in vitro, also in a dose and time dependent manner. The addition of recombinant beta2-microglobulin protein or anti-beta2-microglobulin antibody increased or decreased, respectively, the anchorage independent growth of SN12C cells. The recombinant beta2-microglobulin protein accelerated cell growth via activating phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase, and induced the phosphorylation of Bcl-xL/Bcl-2-associated death promoter. However, treatment with anti-beta2-microglobulin antibody induced cell death by inhibiting the phosphorylation of Akt and extracellular signal-regulated kinase, and activating c-jun N-terminal kinase, resulting in the induction of phosphorylation of B-cell lymphoma 2 and decreased phosphorylation of Bcl-xL/Bcl-2-associated death promoter, leading to apoptosis.

CONCLUSIONS:

Our results demonstrate that beta2-microglobulin has an important role in regulating the growth and survival of renal cell carcinoma cells and anti-beta2-microglobulin antibody offers a potential novel therapy for the treatment of human renal cell carcinoma.

PMID:
17499801
DOI:
10.1016/j.juro.2007.03.007
[PubMed - indexed for MEDLINE]
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