Inhibitors of the ERK signaling pathway cooperate in the anti-proliferative effect of chemotherapeutics in colon cancer cells exposed to PTHrP

MARTIN MARIA JULIA; NOVOA DIAZ MARÍA BELEN; CALVO NATALIA; CARRIERE PEDRO; GENTILI CLAUDIA

Buenos Aires

Congreso; XXXIV Reunión Anual de AAOM; 2017

Asociación Argentina de Osteología y Metabolismo Mineral

PTHrP is expressed in more than 90% of colorectal cancer (CRC) patients. Irinotecan (CPT-11) is approved for the treatment of advanced or recurrent CRC in combination with 5-fluoracil (5-FU); however more than half of the patients response poorly to CPT-11-based therapy. In vitro studies revealed that PTHrP can mediate chemoresistance responses. In human CRC cells, we found that PTHrP, via ERK1/2, induces the activation of RSK and also the phosphorylation and nuclear localization of β-catenin, being both key factors in the growth of CRC. The aim of this work was to study whether PTHrP confers chemoresistance to colon cancer cells and if so, the molecular mechanisms involved in this tumoral behavior. We found that ERK1/2 and β-catenin participate in tumor cell proliferation induced by PTHrP. CPT-11 decreased the number of viable cells; however PTHrP plus CPT-11-treatment resulted in a greater viable cell number respect to CPT-11 treatment, suggesting that PTHrP confers chemoresistance to CRC cells. Moreover, the cytotoxic effect due to CPT-11 was restored when the cells were treated with CPT-11 plus ERK or β-catenin inhibitors in the presence of the hormone, suggesting that the inhibition of both pathways cooperate with CPT-11 in its anti-proliferative effect on cells exposed to PTHrP. Finally, the treatment with an inhibitor of RSK or with 5-FU for 2 days significantly decreased the number of viable cells. However, the combination of 5-FU with the RSK inhibitor further reduced the number of viable cells. These findings might be relevant for understanding the resistance to treatment regimens and the design of new therapeutic strategies aimed at blocking PTHrP action in CRC.