Hyaluronidase activation of c-Jun N-terminal kinase is necessary for protection of L929 fibrosarcoma cells from staurosporine-mediated cell death.
Hyaluronidase counteracts the growth inhibitory function of transforming growth factor beta (TGF-beta), whereas secretion of autocrine TGF-beta and hyaluronidase is necessary for progression and metastasis of various cancers. Whether hyaluronidase and TGF-beta1 induce resistance to staurosporine in L929 fibrosarcoma cells was investigated. When pretreated with TGF-beta1 for 1-2 h, L929 cells resisted staurosporine apoptosis. In contrast, without pretreatment, hyaluronidase protected L929 cells fromstaurosporine apoptosis. Hyaluronidase rapidly activated p42/44 MAPK (or ERK) in L929 cells and TGF-beta1 retarded the activation. Nonetheless, TGF-beta1 synergistically increased hyaluronidase-mediated inhibition of staurosporine apoptosis. Hyaluronidase rapidly activated c-Jun N-terminal kinase (JNK1 and JNK2) in L929 cells in 20 min. Dominant negative JNK1, JNK2, and JNK3 abolished the hyaluronidase inhibition of staurosporine apoptosis, but not the TGF-beta1 protective effect. Unlike the resistance to staurosporine, pretreatment of L929 cells with hyaluronidase is necessary to generate resistance to other anticancer drugs, including doxorubicin, daunorubicin, actinomycin D, and camptothecin, and the induced resistance was also blocked by dominant-negative JNKs. Together, hyaluronidase-mediated JNK activation is necessary to generate resistance to various anticancer drugs in L929 cells.
Chang
N S
NS
Laboratory of Molecular Immunology, Guthrie Research Institute, Guthrie Medical Center, Sayre, Pennsylvania 18840, USA. nschang@inet.guthrie.org
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019556:COS Cells; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D004351:Drug Resistance; D004789:Enzyme Activation; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000378:metabolism* / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016212:Transforming Growth Factor beta; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D006821:Hyaluronoglucosaminidase; D019311:Staurosporine