RAS oncogenes are among the most frequently mutated genes in human cancer, but effective strategies for therapeutic inhibition of the RAS pathway have been elusive. Sprouty1 (SPRY1) is an upstream antagonist of RAS that is activated by extracellular signal-related kinase (ERK), providing a negative feedback loop for RAS signaling, and other evidence suggests that SPRY1 may have a tumor suppressor function. Studies of RAS status in the human childhood tumor rhabdomyosarcoma (RMS) indicated mutations in approximately half of the tumors of the embryonal rhabdomyosarcoma subtype (ERMS) but not the alveolar subtype (ARMS). ERMS tumors also showed overexpression of SPRY1, which was indeed upregulated by mutant RAS. However, we found that, in the presence of mutant RAS, the function of SPRY1 was changed from an antagonist to an agonist of RAS signaling. Thus, SPRY1 supported formation of activated ERK and mitogen-activated protein/ERK kinase and was essential for ERMS cell proliferation and survival. Conversely, silencing of SPRY1 in ERMS cells (but not ARMS cells) abolished their tumorigenicity in mice. Moreover, silencing of SPRY1 caused regression of established ERMS tumors (but not ARMS tumors) formed in xenograft settings. Our findings argue that SPRY1 inhibition can offer a therapeutic strategy to treat childhood RMS and possibly other tumors carrying oncogenic RAS mutations.

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Keywords animal cell, animal experiment, animal model, animal tissue, article, carcinogenicity, cell proliferation, cell survival, controlled study, embryo, enzyme activation, enzyme inhibition, gene mutation, gene silencing, human, human cell, human tissue, male, mitogen activated protein kinase, mouse, nonhuman, nucleotide sequence, oncogene ras, priority journal, protein function, rhabdomyosarcoma, signal transduction, sprouty protein, tumor regression
Persistent URL dx.doi.org/10.1158/0008-5472.CAN-09-2532, hdl.handle.net/1765/19548
Citation
Schaaf, G, Hamdi, M, Zwijnenburg, D, Lakeman, A, Geerts, D, Versteeg, R, & Kool, M. (2010). Silencing of SPRY1 triggers complete regression of rhabdomyosarcoma tumors carrying a mutated RAS gene. Cancer Research, 70(2), 762–771. doi:10.1158/0008-5472.CAN-09-2532