Involvement of ERK1/2, p38 MAPK, and PI3K/Akt signaling pathways in the regulation of cell cycle progression by PTHrP in colon adenocarcinoma cells

Calvo, Natalia; Martín, María Julia; Boland, Ana Russo de; Gentili, Claudia

doi:10.1139/bcb-2013-0106

Cited by 19 publications

(30 citation statements)

References 47 publications

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“…Control conditions were performed by addition of an equivalent volume of DMSO (which is the vehicle of all used inhibitors). In previous works we confirmed the effectiveness of the kinases inhibitors PD 98059 and Ro-318220 (Calvo et al, 2011(Calvo et al, , 2014Martín et al, 2014), whereas PP1 and GSK690693 doses were chosen according to previous works in vitro (Levy et al, 2009;Maat et al, 2009;Saksena et al, 2005).…”

Section: Cell Culture and Treatmentmentioning

confidence: 71%

“…The activation of ERK1/2 signaling is very common in colon cancer and is vital for the growth of CRC cells (Cheruku et al, 2015;Setia et al, 2014), We previously observed that PTHrP stimulates cell proliferation and cell cycle progression through ERK MAPK in tumor intestinal cells (Martín et al, 2014;Calvo et al, 2014). Moreover, our recent studies revealed that PTHrP can promote cell migration through RSK/ERK MAPK in Caco-2 cells and HCT116 cells (Calvo et al, 2017).…”

Section: Pthrp Induces the Phosphorylation And Activation Of Src Kinamentioning

confidence: 96%

“…Experimental cultures were grown to 80% confluence in serum-containing medium, and then cells were serum-deprived 24 h before the addition of 10 −8 M PTHrP (1-34) at different times. This dose of exposure was selected because we previously studied the effects of PTHrP (1-34) 10 −8 M in Caco-2 cells and HCT116 cells expressing PTH/PTHrP receptor (Calvo et al, 2014;Martín et al, 2014). In previous study we showed the relevance of exogenous PTHrP in the tumor intestinal cellular response since we observed that endogenous PTHrP (produced by the tumor cell) did not influence on cellular response (Martín et al, 2014).…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

“…With respect to PKC, during cancer cell proliferation and survival several of their isozymes stimulate survival or proliferation through different signaling pathways such as PI3K/Akt (Kang, 2014). As we previously observed that PTHrP activates PI3K/Akt in tumor intestinal cells (Calvo et al, 2014;Martín et al, 2014), then we first evaluated if PKC and Src signaling pathways are involved in the phosphorylation/activation of Akt induced by PTHrP in these cells. To that end, Caco-2 cells and HCT116 cells were pre-incubated with a specific inhibitor of PKC, Ro-318220 (200 nM) or with a specific inhibitor of Src, PP1 (10 μM) and then treated for 60 min or 1 min with PTHrP, respectively.…”

Section: Pkc Src and Akt Signaling Pathways Modulate The Phosphorylamentioning

confidence: 99%

“…The human colon carcinoma cell line HCT116, another CRC derived cell line, shows a more aggressive phenotype due to hyperactivating mutations in KRAS and PIK3CA genes (Ahmed et al, 2013;Botchkina et al, 2009). We previously showed that in both, Caco-2 cells and HCT116 cells, PTH1R is expressed and that exogenous PTHrP modulates cell cycle progression and exerts proliferative and protective effects via MAPKs and PI3-kinase/Akt signaling pathways (Calvo et al, 2014;Lezcano et al, 2013;Martín et al, 2014). More recently, we obtained evidence that in both cell lines PTHrP induces cell migration via RSK/ERK1/2 signaling pathway but not through p38 MAPK; also the peptide increases the expression of the active form of RSK in HCT116 tumor xenografts (Calvo et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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

Martín

Gigola

Zwenger

et al. 2018

Molecular and Cellular Endocrinology

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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.

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Section: Cell Culture and Treatmentmentioning

confidence: 71%

Section: Pthrp Induces the Phosphorylation And Activation Of Src Kinamentioning

confidence: 96%

Section: Cell Culture and Treatmentmentioning

confidence: 99%

Section: Pkc Src and Akt Signaling Pathways Modulate The Phosphorylamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Martín

Gigola

Zwenger

et al. 2018

Molecular and Cellular Endocrinology

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Role of PTHrP nuclear localization and carboxyl terminus sequences in postnatal spinal cord development

Liu

Wang

et al. 2020

Developmental Neurobiology

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Parathyroid hormone‐related peptide (PTHrP) acts under physiological conditions to regulate normal development of several tissues and organs. The role of PTHrP in spinal cord development has not been characterized. Pthrp knock in (Pthrp KI) mice were genetically modified to produce PTHrP in which there is a deficiency of the nuclear localization sequence (NLS) and C‐terminus. Using this genetically modified mouse model, we have characterized its effect on spinal cord development early postnatally. The spinal cords from Pthrp KI mice displayed a significant reduction in its length, weight, and cross‐sectional area compared to wild‐type controls. Histologically, there was a decreased development of neurons and glial cells that caused decreased cell proliferation and increased apoptosis. The neural stem cells (NSCs) cultures also revealed decreased cell proliferation and differentiation and increased apoptosis. The proposed mechanism of delayed spinal cord development in Pthrp KI mice may be due to alteration in associated pathways in regulation of cell‐division cycles and apoptosis. There was significant downregulation of Bmi‐1 and upregulation of cyclin‐dependent kinase inhibitors p27, p21, and p16 in Pthrp KI animals. We conclude that NLS and C‐terminus peptide segments of PTHrP play an important role in inhibiting cell apoptosis and stimulation of cellular proliferation necessary for normal spinal cord development.

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PTHrP promotes development of mouse preimplantation embryos through the AKT/cyclin D1 pathway and nuclear translocation of HDAC4

Guo

et al. 2021

Journal Cellular Physiology

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Parathyroid hormone‐related protein (PTHrP), the main cause of humoral hypercalcemia in malignancies, promotes cell proliferation and delays terminal cell maturation during embryonic development. Our previous study reported that PTHrP plays important roles in blastocyst formation, pluripotency gene expression, and histone acetylation during mouse preimplantation embryonic development. In this study, we further investigated the mechanism of preimplantation embryonic development regulated by PTHrP. Our results showed that Pthrp depletion decreased both the developmental rate of embryos at the cleavage stage and the cell number of morula‐stage embryos. Pthrp‐depleted embryos had significantly decreased levels of cyclin D1, phospho (p)‐AKT (Thr308) and E2F1. However, Pthrp depletion did not cause significant changes in CDK4, β‐catenin or RUNX2 expression. In addition, our results indicated that Pthrp depletion promoted HDAC4 translocation from the cytoplasm to the nucleus in cleavage‐stage embryos by stimulating the activity of protein phosphatase 2A (PP2A), which resulted in dephosphorylation of HDAC4. Taken together, these results suggest that PTHrP regulates cleavage division progression and blastocyst formation through the AKT/cyclin D1 pathway and that PTHrP modulates histone acetylation patterns through nuclear translocation of HDAC4 via PP2A‐dependent HDAC4 dephosphorylation during preimplantation embryonic development in mice.

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Involvement of ERK1/2, p38 MAPK, and PI3K/Akt signaling pathways in the regulation of cell cycle progression by PTHrP in colon adenocarcinoma cells

Cited by 19 publications

References 47 publications

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

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

Role of PTHrP nuclear localization and carboxyl terminus sequences in postnatal spinal cord development

PTHrP promotes development of mouse preimplantation embryos through the AKT/cyclin D1 pathway and nuclear translocation of HDAC4

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