DIFFERENTIAL SENSITIVITY OF CRC CELLS TO CHEMOTHERAPEUTIC DRUGS: STUDY OF MECHANISMS INVOLVED

NOVOA DÍAZ MB; CARRIERE P; MARTIN MJ; ZWENGER A; CALVO; GENTILI C

Modalidad virtual

Jornada; XXIII JORNADAS ANUALES DE LA SOCIEDAD ARGENTINA DE BIOLOGÍA ?Evolución, desarrollo y cambio tecnológico: impacto sobre el crecimiento de los individuos y la sociedad?.; 2021

Sociedad Argentina de Biología (SAB)

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, and chemoresistance is the main obstacle for the treatment. Parathyroid hormone-related peptide (PTHrP) is a cytokine that is involved in the initiation, growth, and invasion of various carcinomas. In CRC cells, we found that this peptide promotes events related to the aggressive behavior of tumor cells such as chemoresistance to irinotecan (or CPT-11, a drug used for CRC treatment). Based on these antecedents, this work aimed to evaluate whether PTHrP induces resistance to chemotherapeutic agents in the HCT116 cell line derived from CRC, and the molecular mechanisms involved in this process. HCT116 cells were treated with oxaliplatin (10 µM), doxorubicin (5 µM) or 5-fluorouracil (10 µM) in the presence or absence of PTHrP. Trypan blue dye exclusion test showed that oxaliplatin and doxorubicin significantly decrease the number of viable cells. However, PTHrP treatment attenuates the cytotoxicity induced by both drugs. Besides, the antitumor effect of 5-fluorouracil was effective in HCT116 cells but PTHrP did not interfere with its cytotoxicity. We previously observed that, in HCT116 cells, PTHrP activates the signaling pathways of β-catenin and Met (a receptor with tyrosine kinase activity), which are key in the progression of CRC. The inhibition of Met and β-catenin pathways using specific inhibitors restored the cytotoxicity of CPT-11, oxaliplatin, and doxorubicin even in the presence of PTHrP, suggesting that this cytokine decreases the sensitivity of CRC cells to these three drugs through both pathways. To evaluate the impact of the tumor microenvironment on this chemoresistance, we performed the same experiments using a conditioned medium (CM) from the stromal endothelial HMEC-1 cells. Preliminary studies suggested that the of these cells, previously treated with PTHrP, attenuates the cytotoxic effect of the drug CPT-11. This work expands the knowledge of the molecular mechanisms associated with PTHrP-induced chemoresistance in CRC cells.