Glial cell-line derived neurotrophic factor (GDNF) family of ligands confer chemoresistance in a ligand-specific fashion in malignant gliomas.
Glial cell-line derived neurotrophic factor (GDNF) is a neurotrophic factor known to promote neuronal survival of dopaminergic neurons in the embryonic midbrain as well as contribute to carcinogenesis in many cancers. Its ubiquitous presence in the central nervous system suggests a role in the mitogenesis of high-grade astrocytoma. GDNF is overexpressed in glioblastoma cell lines and human gliomas. GFRalpha1b is the predominant spliced receptor isoform in human gliomas and RET9 is the predominant co-receptor. Significantly there is differential overexpression of the GFRalpha1b spliced isoform compared to the GFRalpha1a spliced variant. Pre-treatment of glioblastoma cell lines with GDNF but not the alternative ligand neurturin, promoted mitogenic behaviour and conferred chemoresistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Signaling mapping of BCNU and GDNF suggest that the ability of GDNF to promote Akt activity and inhibit JNK activity may contribute to the increased cellular survival after BCNU chemotherapy.
Ng
Wai Hoe
WH
Department of Biochemistry, Faculty of Medicine, National University of Singapore. wai_hoe_ng@nni.com.sg
Wan
Guo Qiang
GQ
Peng
Zhong Ni
ZN
Too
Heng Phon
HP
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000145:classification* / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005910:Glioma / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008024:Ligands; D019006:Neural Cell Adhesion Molecules; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002330:Carmustine