JNK1 determines the oncogenic or tumor-suppressive activity of the integrin-linked kinase in human rhabdomyosarcoma.
Although most reports describe the protein kinase integrin-linked kinase (ILK) as a proto-oncogene, occasional studies detail opposing functions in the regulation of normal and transformed cell proliferation, differentiation, and apoptosis. Here, we demonstrated that ILK functions as an oncogene in the highly aggressive pediatric sarcoma alveolar rhabdomyosarcoma (ARMS) and as a tumor suppressor in the related embryonal rhabdomyosarcoma (ERMS). These opposing functions hinge on signaling through a noncanonical ILK target, JNK1, to the proto-oncogene c-Jun. RNAi-mediated depletion of ILK induced activation of JNK and its target, c-Jun, resulting in growth of ERMS cells, whereas in ARMS cells, it led to loss of JNK/c-Jun signaling and suppression of growth both in vitro and in vivo. Ectopic expression of the fusion gene characteristic of ARMS (paired box 3-forkhead homolog in rhabdomyosarcoma [PAX3-FKHR]) in ERMS cells was sufficient to convert them to an ARMS signaling phenotype and render ILK activity oncogenic. Furthermore, restoration of JNK1 in ARMS reestablished a tumor-suppressive function for ILK. These findings indicate what we believe to be a novel effector pathway regulated by ILK, provide a mechanism for interconversion of oncogenic and tumor-suppressor functions of a single regulatory protein based on the genetic background of the tumor cells, and suggest a rationale for tailored therapy of rhabdomyosarcoma based on the different activities of ILK.
Durbin
Adam D
AD
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Somers
Gino R
GR
Forrester
Michael
M
Pienkowska
Malgorzata
M
Hannigan
Gregory E
GE
Malkin
David
D
D000818:Animals; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering / Q000235:genetics; D012208:Rhabdomyosarcoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000099200:Scaffold Protein ILK
D048055:Mitogen-Activated Protein Kinase 8; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D000099200:Scaffold Protein ILK; C000715470:MAS1 protein, human; C523321:PAX3-FKHR fusion protein, human