Aktuelle Urol 2006; 37 - V3
DOI: 10.1055/s-2006-947392

Altered beta 1 integrin expression in renal cell carcinoma exposed to valproic acid – disease progression and new theraputic options

J Jones 1, J Makareviæ 1, D Jonas 1, P Baer 1, RA Blaheta 1
  • 1Klinik für Urologie und Kinderurologie, Universitätsklinik Frankfurt

Aim: To elucidate the role of beta1 integrin expression during progression of renal cell carcinoma (RCC).

Materials and methods: The experiments were based on Caki-I and KTC-26 kidney carcinoma cell lines and normal renal proximal tubular epithelial cells (PTC). Alpha 1 to alpha 6 beta 1 integrin subunits were evaluated by RT-PCR and Western blot, and integrin surface expression was analyzed by flow cytometry and confocal microscopy. The expression pattern was correlated to tumor cell growth and adhesion to an endothelial cell monolayer. In order to examine the relevance of integrin alterations on their malignant behavior, tumor cells were treated with the differentiation inducing agent valproic acid (VPA) and modifications of the integrin subunits evaluated. Growth and adhesion characteristics of treated versus non-treated cells were then analyzed.

Results: Caki-I and KTC-26 tumor cells showed rapid cell growth and high adhesion capacity, whereas PTC cells exhibited significantly lower growth and adhesion activity. As compared to PTC cells, Caki-I and KTC-26 cells demonstrated a strikingly altered integrin expression pattern. In addition, alpha3beta1 proteins were found to be distinctly accumulated in both Caki-I and KTC-26 cells. Furthermore, alpha1 and alpha3 coding mRNA were highly active (alpha3 > alpha1), in contrast to alpha2 and alpha6 mRNA which were only moderately detected in both malignant cell lines. VPA application significantly blocked tumor cell proliferation as well as tumor cell attachment to human endothelial cells. Interestingly, blockage of tumor cell proliferation and tumor cell attachment was accompanied by a reduction of the highly elevated integrin expression of Caki I cells to an expression level comparable to the normal (PTC) cells suggesting a strong association between integrin expression and RCC progression.

Conclusion: Based upon our in vitro model, we postulate a direct association between the expression pattern of integrins in RCC and disease progression. Ultimately, identification of integrin overexpression in a subset of RCC patients might serve as an interesting molecular target for treatment with valproic acid.)