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


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.
Nomura
Takeo
T
Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Huang
Wen-Chin
WC
Seo
Seongil
S
Zhau
Haiyen E
HE
Mimata
Hiromitsu
H
Chung
Leland W K
LW
D017209:Apoptosis / Q000502:physiology; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D003114:Colony-Forming Units Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D051025:bcl-Associated Death Protein / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000276:immunology / Q000502:physiology*
D011994:Recombinant Proteins; D051025:bcl-Associated Death Protein; D001613:beta 2-Microglobulin; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases