Crosstalk between a and d PKC isoforms and Retinoic Acid System in malignant phenotype reversion

DAMIAN E. BERARDI; MARIA I. DIAZ BESSONE; PAOLA B. CAMPODÓNICO; CAROLINA FLUMIAN; ELISA D. BAL DE KIER JOFFÉ; ALEJANDRO J. URTREGER; LAURA B. TODARO

San Luis

Congreso; XLVII Reunion Anual Sociedad Argentina de Investigacion en Bioquimica y Biologia Molecular; 2011

Sociedad Argentina de Investigacion en Bioquimica y Biologia Molecular

Retinoic acid (RA) may exert some of their effects on cell differentiation and malignant phenotype reversion through the interaction with some PKCs. We used mammary tumor cell lines LM3 and MDA-MB231 as models. Objetive: study crosstalk between retinoid system and PKC signaling pathway on mechanisms implicated in malignant phenotype reversion. In LM3 cell line, all trans RA induced growth inhibition associated with reduction of pERK and increase nuclear p27. No modulations were observed in MDA-MB231 cells. RA induced an increase in PKCa and PKCd together with nuclear translocation only of PKCd isoform in the murine cell line. In MDA-MB231 cells, both isoforms of PKC were reduced after RA exposure. Pharmacological silencing of PKCa Gö6976 (Gö) and PKCd (Rottlerin) prevented retinoic receptors (RAR) activation by RA in LM3 cells (gene reporter assay). Only PKCd inhibition impaired RA-induced RARa translocation to the nucleus and co-immunoprecipitated with RARa1 after RA exposure. Gö-RA cotreatment decreased cell duplication ratein additive manner respect to each one separately. In in vivo assay the combination therapy reduces the number of lung metastasis. Conclusion: crosstalk PKC/retinoids is implicated in growth inhibition through RA transcripcion genes induction. Combined treatment with Retinoids and PKCa modulators could be considered for PKCa positive breast cancer patients.