Involvement of receptor tyrosine phosphatase DEP-1 mediated PI3K-cofilin signaling pathway in sorafenib-induced cytoskeletal rearrangement in hepatoma cells.
Sorafenib is a multikinase inhibitor that has been reported to induce cell growth inhibition through the Raf-MAPK signaling pathway. We now report that Sorafenib treatment of Hep3B and PLC/PRF/5 human hepatoma cells also results in morphological changes and cell detachment in culture. Actin cytoskeletal analysis of Sorafenib-exposed Hep3B cells showed a loss of polymerized F-actin and a concomitant increase in unpolymerized G-actin, implying that Sorafenib-induced cell shape changes may be related to actin cytoskeletal rearrangement by inhibiting actin polymerization. Cofilin, an actin depolymerization factor, was found to be dephosphorylated and thus activated by Sorafenib, consistent with the observed increase in unpolymerized G-actin. In examining likely mechanisms, we found that Sorafenib induced activation of the cofilin phosphatase Slingshot 1 (SSH-1), since endogenous SSH-1 from Sorafenib-treated Hep3B cells was able to dephosphorylate cofilin in a concentration dependent manner. The activation of SSH-1 by Sorafenib is probably regulated by the PI3K pathway, since Sorafenib can induce PI3K and its substrate Akt phosphorylation, and both PI3K inhibitors Ly294002 and wortmannin antagonized Sorafenib-mediated cofilin dephosphorylation. Furthermore, we found that Sorafenib induced c-Met phosphorylation at Tyr-1349 but not Tyr-1234, which is probably mediated by inhibition of receptor tyrosine phosphatase density enhanced phosphatase-1 (DEP-1). Our data provide evidence that besides inhibition of the Raf-MAPK pathway, Sorafenib might also regulate hepatoma cell growth via alteration of receptor-mediated cytoskeletal rearrangement.
Wang
Ziqiu
Z
Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. ziqiu.wang@jefferson.edu
Wang
Meifang
M
Carr
Brian I
BI
D000199:Actins / Q000378:metabolism; D001557:Benzenesulfonates / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology; D051338:Cofilin 1 / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology; D008954:Models, Biological; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib
D000199:Actins; D001557:Benzenesulfonates; D051338:Cofilin 1; D010671:Phenylurea Compounds; D011725:Pyridines; D019000:Phosphotyrosine; D009536:Niacinamide; D000077157:Sorafenib; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D010749:Phosphoprotein Phosphatases; C484329:SSH1 protein, human; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3