PTHrP induces tumorigenic beta-catenin pathway independently of Wnt signaling in colon cancer cells.

NOVOA DIAZ, BELEN; MARTÍN, MA. JULIA; CARRIERE, PEDRO; CALVO, NATALIA; GENTILI, CLAUDIA

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedades de Biociencias

There is evidence that PTHrP is implicated in different cancers such as colorectal cancer (CCR). CCR is the second most common cancer in Argentina, according to data from the National Cancer Institute. Although great progress has been made in the diagnosis and therapy of CCR, the survival rate remains low. It is known that β-catenin is a protein which plays a key role in maintaining the growth and proliferation of CCR. In tumor intestinal cells treated with PTHrP, we previously found that Akt and ERK1/2 signaling pathway are involved in the phosphorylation and subsequent nuclear translocation of β-catenin. The aim of this study was to further investigate the molecular mechanisms involved in these processes induced by the hormone employing two cell lines derived from human colorectal cancer, Caco-2 and HCT116. Results by Western blot analysis suggest that PKC, Src and p38 MAPK signaling pathways modulate the phosphorylation of β-catenin induced by PTHrP. Once in the nucleus β-catenin can bind to transcription factors, such as LEF-1 and TCF family members, promoting the expression of genes such as c-Myc and cyclin D. Immunocytochemistry analysis suggest that PTHrP induces LEF-1 protein expression and also promotes the association of β-catenin with this transcription factor. However, the protein-protein interaction between β-catenin and Transcription factor 7-like 2 (TCFL2) observed in basal conditions is not modified by PTHrP. These results may be correlated with our previous reports where PTHrP also increases protein levels of cyclin D and c-Myc through ERK1/2. Finally, employing iCRT 14, a specific inhibitor of gene transcription induced by β-catenin, we found that β-catenin participates in tumor cell proliferation induced by PTHrP. Investigation of the underlying mechanisms for the tumorigenesis of CCR will facilitate the diagnosis and therapy of this disease.