Involvement of PKCa inhibition and Retinoid system induction in the mammary cancer stem cell biology

DAMIAN E. BERARDI; MARÍA INÉS DÍAZ BESSONE; CAROLINA FLUMIAN; STÉFANO M. CIRIGLIANO; ELISA BAL DE KIER JOFFÉ; ALEJANDRO J. URTREGER; LAURA B. TODARO

Rosario

Congreso; L Reunion Anual Sociedad Argentina de Investigacion en Bioquimica y Biologia Molecular; 2014

Sociedad Argentina de Investigacion en Bioquimica y Biologia Molecular

It has been established that retinoids exert some of their effects on cell differentiation and malignant phenotype reversion through the interaction with different members of the PKC family. Objective: to study the modulation of the expression of PKCa and retinoic acid receptors (RAR) by Retinoic Acid (RA) and to analyze the effect of RA+PKCa inhibitor on proliferation, self-renewal and differentiation of cancer stem cells (CSC) from triple negative mammary cell line LM38-LP. By RT-PCR we found that RA decreased PKCa and increased RARb and RARg in CSC. RARg increase was abrogated by the addition of PKCa inhibitor. RA and PKCa inhibitor synergized to reduce CSC growth (number and diameter of mammospheres). RA treatment showed an increment in self-renewal (secondary mammospheres formation) and clonogenic capacity of LM38-LP CSC, via RARg. This effect was reversed when PKCa activity was inhibited. In a matrigel 3D culture assay, CSC generated large undifferentiated structures while PKCa activity inhibition together with RA treatment led to the formation of small and differentiated structures with evidence of cell death. Our data suggest that the CSC differentiation, reduced self-renewal and clonogenic capacity, induced by the pharmacological inhibition of PKCa together with the activation of retinoic system could be possibly through the modulation of RARg.