SURAMIN, A PROTEIN-KINASE-C INHIBITOR, IMPAIRS HEPATIC REGENERATION

Citation
Ja. Daller et al., SURAMIN, A PROTEIN-KINASE-C INHIBITOR, IMPAIRS HEPATIC REGENERATION, Cell growth & differentiation, 5(7), 1994, pp. 761-767
Citations number
66
Categorie Soggetti
Biology,"Cytology & Histology
ISSN journal
10449523
Volume
5
Issue
7
Year of publication
1994
Pages
761 - 767
Database
ISI
SICI code
1044-9523(1994)5:7<761:SAPIIH>2.0.ZU;2-M
Abstract
Previously we have shown that partial hepatectomy (PH) or exposure of the liver to the mitogen prolactin induces activation of hepatic prote in kinase C (PKC). Here, we used suramin, an antitrypanosomal and chem otherapeutic drug which inhibits that enzyme, as a probe of PKC signal transduction in the regenerative response after PH in the rat. Surami n was administered i.p. in nonhepatotoxic doses of 20 to 160 mg/kg 14 days prior to PH. Three measures of hepatic DNA synthesis or cell divi sion, thymidine kinase activity, [H-3]thymidine incorporation, and mit otic index were inhibited in a dose-dependent fashion, Baseline PKC ac tivity, in both the cytosolic and particulate fractions, was unchanged by suramin. After PH, PKC activation, signalled by an increase in act ivity in the particulate fraction, was observed in control rats at 30 and 60 min. However, rats which had previously received suramin demons trated dose-dependent inhibition of PKC activation. Suramin is known t o also disrupt the binding of certain growth factors to their receptor s. But if inhibition of PKC activation were conferred by interference with growth factor-receptor binding by suramin, then the generation of diacylglycerol, the second messenger for PKC activation, should likew ise be impaired. However, we observed that the diacylglycerol mass gen erated at 15, 30, and 45 min after PH was not altered by suramin pretr eatment. We conclude that the diminution in DNA synthesis after PH by suramin is likely the consequence of direct inhibition of PKC, suggest ing that PKC activation is an important, perhaps obligatory, signal tr ansduction event in liver regeneration.