Molecular mechanisms related to chemoresistance of colorectal cancer cells

CARRIERE, PEDRO; GIGOLA GRACIELA; ZWENGER ARIEL; CALVO NATALIA; GENTILI CLAUDIA; NOVOA DÍAZ MARÍA BELEN; MARTIN MARIA JULIA; GOMEZ LUIS

Congreso; Molecular analysis for precision oncology virtual congress (MAP 2020 Virtual Congress); 2020

European Society for Medical Oncology

Colorectal cancer (CRC) is one of the major causes of cancer death worldwide. Chemoresistance is frequent in the treatment of CRC patients. The parathyroid hormone related peptide (PTHrP) is a bioactive factor in the initiation, growth, and invasion of various carcinomas. In HCT116 cells derived from human CRC, we found that PTHrP exerts proliferative and protective effects, induces cell migration and promotes tumor-associated angiogenesis. PTHrP also increases chemoresistance to Irinotecan (or CPT-11, a drug for CRC treatment) through ERK1/2 MAPK. In vivo PTHrP administration increases the expression of several markers related to tumorigenic events. Based on these antecedents, the aim of this work was to explore if PTHrP induces resistance to other chemotherapeutic agents in CRC cells and if so, to evaluate the molecular mechanisms involved in these processes. HCT116 cells were treated only with Oxaliplatin (10 uM) or in combination with PTHrP. Trypan blue dye exclusion test revealed that Oxaliplatin significantly decreases the number of viable HCT116 cells. However, PTHrP treatment in HCT116 cells attenuated the cytotoxicity induced by Oxaliplatin. Similar experiments were performed with 5-FU (10 uM). HCT116 cells responded to the antitumor effect of 5-FU but PTHrP did not interfere with its cytotoxicity. Met is a receptor with dysregulated expression and signaling in CRC. Previously we found that PTHrP activated Met through MAPK in HCT116 cells and also increased Met protein levels in vivo. Herein we found by means of Trypan blue test that the inhibition of Met pathway restored the cytotoxicity of CPT-11 or Oxaliplatin in HCT116 cells, even in the presence of PTHrP suggesting that PTHrP attenuates the anti-tumor effect of both drugs through the Met pathway. This work expands the knowledge of the molecular mechanisms associated with the chemoresistance of CRC cells induced by PTHrP.Funding: ANPCyT (PICT-2013-1441), CONICET (PIP11220150100350), Instituto Nacional del Cáncer (RESOL-2016-1006-E-APN-MS) and Universidad Nacional del Sur (PGI: 24/B188; PGI: 24/B230), Argentina.