Potential therapeutic targets for growth arrest of colorectal cancer cells exposed to PTHrP

Abstract

Although PTHrP is implicated in several cancers, its role in chemoresistance is not fully elucidated. We found that in CRC cells, PTHrP exerts proliferative and protective effects and induces cell migration. The aim of this work was to further study the effects of PTHrP in CRC cells. Herein we evidenced, for the first time, that PTHrP induces resistance to CPT-11 in Caco-2 and HCT116 cells; although both cell lines responded to the drug through different molecular mechanisms, the chemoresistance by PTHrP in these models is mediated through ERK, which in turn is activated by PCK, Src and Akt. Moreover, continue administration of PTHrP in nude mice xenografts increased the protein levels of this MAPK and of other markers related to tumorigenic events. The understanding of the molecular mechanisms leading to ERK 1/2 activation and the study of ERK targets may facilitate the development of new therapeutic strategies for CRC treatment.

PTHrP treatment of colon cancer cells promotes tumor associated-angiogenesis by the effect of VEGF

“…We evaluated if the response of HMEC-1 cells observed previously by us is the same or is different when these cells were exposed to TCMs which were pre-incubated for h at °C with the anti-VEGF antibody or with an appropriate isotype-matched control rabbit IgG. As shown in Figures 6A, B In previous studies, we obtained evidence that the hormone increases the proliferation, migration, survival and chemoresistance via MAPKs and PI3K/AKT signaling pathways in the colon cancer Caco-2 cells and HCT116 cells (Lezcano et al, 2013;Martín et al, 2014;Calvo et al, 2014;Calvo et al, 2017;Martín et al, 2018). ERK1/2 and AKT are central proteins in many cellular pathways leading to angiogenesis (Xu et al, 2015;Dong et al, 2017).…”

“…CRC is one of the main causes of death for cancer in the world (Siegelet al, 2017). chemoresistance and has a protective effect in conditions of apoptosis by the regulation of these signaling pathways (Lezcano et al, 2013;Martín et al, 2014;Calvo et al, 2014;Calvo et al, 2017;Martín et al, 2018). We think that other…”

“…Several of the signaling pathways that may participate in the regulation of proangiogenic factors (Xu et al, 2015;Hammoud et al, 2016;Dong et al, 2017) are modulated by PTHrP in cells derived from CRC (Lezcano et al, 2013;Martín et al, 2014;Calvo et al, 2014;Calvo et al, 2017;Martín et al, 2018). Figure 1A).…”

“…Recently, we found that PTHrP induces chemoresistance in Caco-2 and HCT116 cells through mitogenic signaling pathways such ERK and Akt (Martin et al, 2018). Also, the administration of PTHrP in HCT xenografts of nude mice, increased the expression of RSK and others markers related to tumorigenic events (Calvo et al, 2017;Martín et al, 2018).…”

Involvement of parathyroid hormone-related peptide in the aggressive phenotype of colorectal cancer cells

“…By the implementation of multiple assays, we found that PTHrP (1-34) stimulates the cell cycle progression and proliferation of Caco-2 cells[ 37 , 38 ]. In line with these results, we reported similar effects induced by the cytokine in HCT116 cells, a CRC-derived cell line more undifferentiated and aggressive concerning Caco-2 cells, which also expresses PTHR1[ 39 ]. Despite the notable differences between Caco-2 cell and HCT116 cell phenotypes, the molecular mechanisms leading to these responses to the peptide in both CRC cells were similar and implied the activation of well-known deregulated pathways in CRC.…”