Continuous PTHrP administration in colorectal cancer cells xenografts increases positive regulators levels of cell proliferation

GIGOLA G; GENTIL F; GENTILI C; MARTIN MJ; MATURI H; CARRIERE P; NOVOA DÍAZ B; CARRIQUIBORDE M; CALVO N

Ciudad Autónoma de Buenos Aires

Congreso; REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS. LXII Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC).; 2017

REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS. Sociedad Argentina de Investigación Clínica (SAIC)

PTHrP has been widely studied because this hormone has an important role in fetus development and adult tissues homeostasis. Today, it is recognized for its endocrine, paracrine and autocrine modes of action. PTHrP was found to be expressed in numerous types of cancer and in more than 90% of colon cancer patients. It has been shown that HCT116 cells, derived from human colorectal carcinoma (CRC), are tumorigenic in nude mice and we previously demonstrated that the continuous administration of PTHrP (40 µg/kg) in HCT116 cells xenografts of these animals promotes the formation and tumor growth and also increased the expression of cyclin D1, a positive regulator of cell cycle progression. The aim of this study was to investigate if the levels of other mitogenic markers changed in response to PTHrP administration employing the same murine model. We found by immunohistochemistry analysis that the hormonal exposure increased the immunoreactivity scores of the active form of RSK kinase and the activated and total forms of ERK 1/2 MAPK, which are involved in the progress of many cancers, including CRC. Moreover CREB/ATF-1 expression was incremented by PTHrP and as expected, the localization of these transcription factors was nuclear whereas active RSK and active and total ERK 1/2 MAPKs were observed in the cytoplasm and nucleus of HCT116 cells. Finally, the expression of the pro-angiogenic factor VEGF was not modified by the peptide at least at the times studied. The present investigation provides, to our knowledge, additional evidence demonstrating that exogenous PTHrP regulates signaling pathways associated with proliferation in animal models. Taken together, these findings emphasize the endocrine/paracrine action of the hormone in in vivo models.