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.