Enhancement of growth-promoting activity in extract from uterine cancers by protein kinase C in human endometrial fibroblasts.
Uterine cervical and corpus cancers have been reported to synthesize and secrete a putative peptide mitogen, which elicits a potent proliferative response in fibroblasts by a mechanism independent of phosphoinositide turnover. The extract from human uterine cervical cancer stimulated [3H]thymidine incorporation into human endometrial fibroblasts in a dose-dependent manner. Concomitant exposure of the fibroblasts to thrombin or fibroblast growth factor (FGF) led to synergistic enhancement of the extract-stimulated [3H]thymidine incorporation into fibroblasts. An apparent maximal activity of the extract in the presence of thrombin or FGF was 2-fold higher than that in the absence of them, implying that thrombin or FGF acted at a stage after the interaction of the mitogen in the extract with its specific receptor. Insulin or epidermal growth factor failed to augment the growth-promoting activity in the extract. The stimulatory action of thrombin or FGF was mimicked by protein kinase C activators, phorbol-12-myristate-13-acetate (PMA) or 1-oleoyl-2-acetyl glycerol, but not by Ca2+ ionophore A23187. When the fibroblasts were first exposed to the extract for 4 h and then to PMA, PMA succeeded to augment the mitogenic activity in the same manner. The identical effects of protein kinase C activators with thrombin or FGF suggested that both types of ligand share a similar signaling cascade of action, activation of protein kinase C. These results demonstrated that the growth-promoting activity in uterine cancer extract could be enhanced by the agents which promote phosphoinositide metabolism through activation of protein kinase C. These findings could give a new insight into pathophysiology of the interaction between malignant cells and their stromal cells, fibroblasts.
Imai
A
A
Department of Obstetrics and Gynecology, Gifu University School of Medicine, Japan.
Matsunami
K
K
Ohno
T
T
Tamaya
T
T
D004717:Endometrium / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005346:Fibroblast Growth Factors / Q000502:physiology; D005347:Fibroblasts / Q000473:pathology*; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D011493:Protein Kinase C / Q000096:biosynthesis*; D013917:Thrombin / Q000502:physiology; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000737:chemistry / Q000378:metabolism*
D006133:Growth Substances; D005346:Fibroblast Growth Factors; D011493:Protein Kinase C; D013917:Thrombin