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 DÍAZ MARÍA BELEN; CALVO NATALIA; CARRIERE, PEDRO; GENTILI CLAUDIA

CABA

Congreso; XXXIV Reunión Anual de la Asociación Argentina de Osteología y Metabolismo Mineral (AAOMM); 2017

Asociacion Argentina de Osteologia y Metabolismo Mineral (AAOMM)

PTHrP is expressed in more than 90% of colorectal cancer (CRC) patients. CCR is the second most common cancer in Argentina. Irinotecan (CPT-11) is approved worldwide 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 Caco-2 and HCT116 cell lines, both derived from human CRC, we found that PTHrP, via ERK1/2, induces the activation of RSK and also the phosphorylation and subsequent nuclear localization of β-catenin, being both key factors in maintaining the growth of CRC. Therefore 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 HCT116 cells; however when the cells were treated with PTHrP plus CPT-11 the number of viable cells was greater than the number of viable cells treated with CPT-11 alone, suggesting that PTHrP confers chemoresistance to colon cancer cells. However, the inhibition of cell growth due to chemotherapeutic treatment alone 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. In line with these observations, the treatment with an inhibitor of RSK or with 5-FU for 2 days significantly decreased the number of viable HCT116 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.