title: 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.
authors.affiliation: Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239-3098, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kikuchi
authors.forename: A
authors.initials: A
authors.lastname: Soundararajan
authors.forename: L A
authors.initials: LA
authors.lastname: Zarzabal
authors.forename: C R
authors.initials: CR
authors.lastname: Weems
authors.forename: L D
authors.initials: LD
authors.lastname: Nelon
authors.forename: S T
authors.initials: ST
authors.lastname: Hampton
authors.forename: J E
authors.initials: JE
authors.lastname: Michalek
authors.forename: B P
authors.initials: BP
authors.lastname: Rubin
authors.forename: A P
authors.initials: AP
authors.lastname: Fields
authors.forename: C
authors.initials: C
authors.lastname: Keller
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D004357:Drug Synergism; D016195:G2 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006052:Gold Sodium Thiomalate / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018232:Rhabdomyosarcoma, Alveolar / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use; D000099293:Protein Kinase C-lambda
chemical_list: D006052:Gold Sodium Thiomalate; D007527:Isoenzymes; D011493:Protein Kinase C; D034741:RNA, Small Interfering; D014750:Vincristine; D000099293:Protein Kinase C-lambda