Protein kinase C iota as a therapeutic target in alveolar rhabdomyosarcoma

K. Kikuchi, A. Soundararajan, L. A. Zarzabal, C. R. Weems, L. D. Nelon, S. T. Hampton, J. E. Michalek, B. P. Rubin, A. P. Fields, C. Keller

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)286-295
Number of pages10
JournalOncogene
Volume32
Issue number3
DOIs
StatePublished - Jan 17 2013

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Kikuchi, K., Soundararajan, A., Zarzabal, L. A., Weems, C. R., Nelon, L. D., Hampton, S. T., Michalek, J. E., Rubin, B. P., Fields, A. P., & Keller, C. (2013). Protein kinase C iota as a therapeutic target in alveolar rhabdomyosarcoma. Oncogene, 32(3), 286-295. https://doi.org/10.1038/onc.2012.46