Altered expression of beta1 integrins in renal carcinoma cell lines exposed to the differentiation inducer valproic acid.
Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney. Adhesion receptors of the beta1 integrin family are assumed to be involved in carcinogenesis, but it is not clear how they contribute to RCC progression. In an in vitro model, we evaluated growth and adhesion capacity of Caki-I and KTC-26 kidney carcinoma cell lines compared to normal renal proximal tubular epithelial cells (PTC). alpha1-alpha6beta1 integrin subunits in malignant and non-malignant cells were evaluated by Western blotting and RT-PCR, integrin surface expression was measured by flow cytometry and confocal microscopy. Additionally, tumor cells were allowed to re-differentiate in the presence of valproic acid (VPA) and dynamic alterations of the integrin profile were analyzed. Caki-I and KTC-26 were characterized by accelerated proliferation and adhesion to an endothelial cell monolayer, compared to PTC cells. The integrin beta1 repertoire in RCC cell lines was significantly different from that detected in PTC, and included down-regulated alpha2 and alpha6, but up-regulated alpha1, alpha3 and alpha5 proteins. VPA application reduced tumor malignancy which was evidenced by reduced cell growth and adhesion capacity. The reduction in tumor malignancy was paralleled by the integrin expression profile of renal tumor cells 'matching' the pattern seen in PTC. We assume that a sensitive integrin balance exists in normal renal epithelial cells, and that dysregulation of the 'physiological' receptor equipment drives these cells towards malignancy. VPA acted on all investigated integrin subtypes and restored the receptor pattern typical for non-malignant cells. Therefore, VPA may represent a novel therapeutic option in RCC treatment.
Oertl
Anton
A
Zentrum der Chirurgie, Klinik für Urologie und Kinderurologie, J.W. Goethe-University, D-60590 Frankfurt am Main, Germany.
Relja
Borna
B
Makarevic
Jasmina
J
Weich
Eva
E
Höfler
Sonja
S
Jones
Jon
J
Jonas
Dietger
D
Bratzke
Hansjürgen
H
Baer
Patrick C
PC
Blaheta
Roman A
RA
D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology; D014635:Valproic Acid / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D039001:Integrin alpha Chains; D019012:Integrin beta1; D014635:Valproic Acid