Protein-kinase-C inhibitor calphostin C reduces B16 amelanotic melanoma cell adhesion to endothelium and lung colonization.
We recently reported that the Ca(2+)- and phospholipid-dependent protein kinase, protein kinase C (PKC), was involved in rat Walker carcinosarcoma cell adhesion to large-vessel endothelium. We extended our studies to explore the role of this kinase in the adhesion to small-vessel endothelium and lung colonization of murine B16 amelanotic melanoma (B16a). Subpopulations of B16a cells, which differ in lung-colonization potentials, were isolated by centrifugal elutriation from solid tumors. In this study, we demonstrate that cells from a high metastatic sub-population (HM340), when compared with cells from a low metastatic sub-population (LM180), exhibit elevated levels of total cellular as well as membrane-bound PKC. The increase in PKC in cells from the HM340 correlates positively to their increased ability to adhere to murine pulmonary-microvessel endothelial-cell monolayer, and to form pulmonary colonies in syngeneic mice. Calphostin C, a potent and selective PKC inhibitor, decreases in a dose-dependent manner the adhesion to endothelium and the lung colonization of cells from both the low and the high metastatic sub-populations with IC50 at sub-micromolar concentrations. In conclusion, our results suggest that PKC may be a key element in regulating tumor-cell metastasis and that PKC inhibitors may be anti-metastatic agents.
Liu
B
B
Department of Radiation Oncology, Wayne State University, Detroit, MI.
Renaud
C
C
Nelson
K K
KK
Chen
Y Q
YQ
Bazaz
R
R
Kowynia
J
J
Timar
J
J
Diglio
C A
CA
Honn
K V
KV
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000818:Animals; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000502:physiology*; D006893:Hydroxyeicosatetraenoic Acids / Q000032:analysis; D008175:Lung Neoplasms / Q000556:secondary*; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D009281:Naphthalenes; D011083:Polycyclic Compounds / Q000494:pharmacology*; D011493:Protein Kinase C / Q000032:analysis / Q000037:antagonists & inhibitors*
D006893:Hydroxyeicosatetraenoic Acids; D009281:Naphthalenes; D011083:Polycyclic Compounds; C061465:calphostin complex; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D011493:Protein Kinase C