Role of Src signal transduction pathways in scatter factor-mediated cellular protection.
Scatter factor (SF) (hepatocyte growth factor) is a pleiotrophic cytokine that accumulates in tumors, where it may induce invasion, angiogenesis, and chemoresistance. We have studied the mechanisms by which SF and its receptor (c-Met) protect cells against the DNA-damaging agent adriamycin (ADR) as a model for chemoresistance of SF/c-Met-overexpressing tumors. Previous studies identified a phosphatidylinositol 3-kinase/c-Akt/Pak1/NF-kappaB cell survival pathway in DU-145 prostate cancer and Madin-Darby canine kidney epithelial cells. Here we studied Src signaling pathways involved in SF cell protection. Src enhanced basal and SF stimulated NF-kappaB activity and SF protection against ADR, in a manner dependent upon its kinase and Src homology 3 domains; and endogenous Src was required for SF stimulation of NF-kappaB activity and cell protection. The ability of Src to enhance SF stimulation of NF-kappaB activity was due, in part, to its ability to stimulate Akt and IkappaB kinase activity; and Src-mediated stimulation of NF-kappaB was due, in part, to a Rac1/MKK3/6/p38 pathway and was Akt-dependent. SF caused the activation of Src and the Rac1 effector Pak1. Furthermore, SF induced activating phosphorylations of MKK3, MKK6, and p38 within the c-Met signalsome in an Src-dependent manner. The NF-kappaB-inducing kinase was found to act downstream of TAK1 (transforming growth factor-beta-activated kinase 1) as a mediator of SF- and Src-stimulated NF-kappaB activity. Finally, the Src/Rac1/MKK3/6/p38 and Src/TAK1/NF-kappaB-inducing kinase pathways exhibited cross-talk at the level of MKK3. These findings delineate some novel signaling pathways for SF-mediated resistance to ADR.
Fan
Saijun
S
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
Meng
Qinghui
Q
Laterra
John J
JJ
Rosen
Eliot M
EM
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D004285:Dogs; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D048669:MAP Kinase Kinase 6; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D018909:src Homology Domains; D000099151:MAP Kinase Kinase Kinase 7
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D017228:Hepatocyte Growth Factor; D051550:I-kappa B Kinase; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D016392:Proto-Oncogene Proteins pp60(c-src); D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; D000099151:MAP Kinase Kinase Kinase 7; C066855:HGF protein, human; C107953:RAC1 protein, human; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human