<i>S</i>-Allyl-L-cysteine Promotes Cell Proliferation by Stimulating Growth Hormone Receptor/Janus Kinase 2/Phospholipase C Pathways and Promoting Insulin-Like Growth Factor Type-I Secretion in Primary Cultures of Adult Rat Hepatocytes

Abstract

The mechanism of insulin-like growth factor type-I (IGF-I) secretion stimulated by S-allyl-L-cysteine (SAC) was investigated as part of a study of SAC-induced DNA synthesis and cell proliferation in primary cultures of adult rat hepatocytes. When 10 6 M SAC was added to the culture, the amount of IGF-I in the medium was significantly increased at 10 min. The peak IGF-I level (140 pg/mL) was observed 20 min after SAC stimulation. The SAC-induced IGF-I secretion was completely suppressed by a selective Janus kinase 2 (JAK2) inhibitor (TG101209), a selective phospholipase C (PLC) inhibitor (U-73122), an intracellular Ca 2 chelating agent (BAPTA-AM), and a granule secretion inhibitor (somatostatin). On the other hand, 10 6 M SAC-stimulated hepatocytes showed increased intracellular Ca 2 concentration in a time-dependent manner from 0 to 10 min. Phosphorylation of SAC-induced JAK2 and IGF-I receptor tyrosine kinase (RTK) was completely suppressed by TG101209. In addition, U-73122, BAPTA-AM, and somatostatin did not suppress SAC-induced JAK2 phosphorylation, but significantly suppressed SAC-induced IGF-I RTK phosphorylation. Furthermore, binding of the monoclonal antibody against growth hormone (GH) to GH receptor was dosedependently suppressed by SAC on immunofluorescence. These results showed that SAC promotes cell proliferation by stimulating GH receptor/JAK2/phospholipase C pathways and promoting autocrine secretion of IGF-I in primary cultures of adult rat hepatocytes.