Regulation of beta1 integrin expression by PKCepsilon in renal cancer cells.
Polarized cell movement represents an essential prerequisite for the progression and metastasis of malignant diseases. Protein kinase C (PKC) which physically associates with integrins has been implicated in the promotion of a migratory cell phenotype. In order to identify a direct link between PKC and integrins in renal cell carcinoma (RCC) the influence of PKC isoforms on integrin expression and possible consequences on proliferation and cell migration was analyzed in RCC cells. The constitutive expression of the PKC isoforms alpha, betaI, betaII, gamma, delta, epsilon, eta, theta, xi, lambda and micro was determined in the RCC cell line CCF-RC1. In addition, the influence of PKC inhibitors RO31-8220, GF109203X and GO6976 on the beta1, beta2 and beta3 integrin expression and cell proliferation of RCC cells was investigated by flow cytometry and by BrdU incorporation, respectively. Furthermore, the motility of CCF-RC1 cells was assessed through chamber chemotaxis analysis. All PKC isoforms tested were expressed in CCF-RC1 cells with the exception of PKClambda and theta. The PKC inhibitor RO31-8220 reduced beta1 integrin expression by 92% and inhibited proliferation by 42% of untreated cells, whereas cell migration remained uninfluenced by RO31-8220. GF109203X and GO6976 reduced beta1 integrin expression to approximately 50% of untreated cells. In contrast, beta2 and beta3 integrins were only weakly affected by RO31-8220, GF109203X and GO6976 treatment. The most significant influence on beta1 integrin expression was obtained by the PKC inhibitor RO31-8220. This leads to the assumption that PKCepsilon is involved in the regulation of beta1 integrin expression. Downregulation of beta1 integrins by RO31-8220 was associated with reduced proliferation, but did not influence migration. These findings provide a conceptual basis for treatment of renal cell carcinoma by interfering with tumor cell proliferation.
Brenner
Walburgis
W
Department of Urology, University of Mainz, D-55131 Mainz, Germany. brenner@mail.uni-mainz.de
Benzing
Frank
F
Gudejko-Thiel
Justine
J
Fischer
Renate
R
Färber
Gloria
G
Hengstler
Jan G
JG
Seliger
Barbara
B
Thüroff
Joachim W
JW
D018821:CD18 Antigens / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D019012:Integrin beta1 / Q000235:genetics*; D039661:Integrin beta3 / Q000235:genetics; D007680:Kidney Neoplasms / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051744:Protein Kinase C-epsilon
D018821:CD18 Antigens; D007211:Indoles; D019012:Integrin beta1; D039661:Integrin beta3; C497255:PRKCE protein, human; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; C064758:Ro 31-8220