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Protein kinase C iota as a therapeutic target in alveolar rhabdomyosarcoma

Abstract

Alveolar rhabdomyosarcoma is an aggressive pediatric cancer exhibiting skeletal-muscle differentiation. New therapeutic targets are required to improve the dismal prognosis for invasive or metastatic alveolar rhabdomyosarcoma. Protein kinase C iota (PKCι) has been shown to have an important role in tumorigenesis of many cancers, but little is known about its role in rhabdomyosarcoma. Our gene-expression studies in human tumor samples revealed overexpression of PRKCI. We confirmed overexpression of PKCι at the mRNA and protein levels using our conditional mouse model that authentically recapitulates the progression of rhabdomyosarcoma in humans. Inhibition of Prkci by RNA interference resulted in a dramatic decrease in anchorage-independent colony formation. Interestingly, treatment of primary cell cultures using aurothiomalate (ATM), which is a gold-containing classical anti-rheumatic agent and a PKCι-specific inhibitor, resulted in decreased interaction between PKCι and Par6, decreased Rac1 activity and reduced cell viability at clinically relevant concentrations. Moreover, co-treatment with ATM and vincristine (VCR), a microtubule inhibitor currently used in rhabdomyosarcoma treatment regimens, resulted in a combination index of 0.470–0.793 through cooperative accumulation of non-proliferative multinuclear cells in the G2/M phase, indicating that these two drugs synergize. For in vivo tumor growth inhibition studies, ATM demonstrated a trend toward enhanced VCR sensitivity. Overall, these results suggest that PKCι is functionally important in alveolar rhabdomyosarcoma anchorage-independent growth and tumor-cell proliferation and that combination therapy with ATM and microtubule inhibitors holds promise for the treatment of alveolar rhabdomyosarcoma.

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Acknowledgements

This work was supported by NIH/NCI Grant 1R01CA133229-04 and -05 awarded to CK, NIH/NCI Grant 4R01CA081436-13 and the V Foundation for Cancer Research awarded to APF. Human tissue samples were provided by the Pediatric Cooperative Human Tissue network, which is funded by the National Cancer Institute. The Developmental Studies Hybridoma Bank is developed under the auspices of the NICHD and maintained by the University of Iowa, Iowa City, IA, USA.

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Kikuchi, K., Soundararajan, A., Zarzabal, L. et al. Protein kinase C iota as a therapeutic target in alveolar rhabdomyosarcoma. Oncogene 32, 286–295 (2013). https://doi.org/10.1038/onc.2012.46

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  • DOI: https://doi.org/10.1038/onc.2012.46

Keywords

  • alveolar rhabdomyosarcoma
  • protein kinase C iota
  • Rac1
  • mitosis
  • aurothiomalate
  • vincristine

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