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Orthovanadate-induced cell death in RET/PTC1-harboring cancer cells involves the activation of caspases and altered signaling through PI3K/Akt/mTOR.

Abstract：

AIMS:Oncogenic RET/PTC1 chromosomal rearrangements are hallmarks of thyroid papillary carcinoma. The resulting protein, mainly through tyrosine 451, is responsible for the activation of pathways controlling cell survival, including the PI3K/Akt/mTOR cascade. Vanadium compounds were shown to have anti-neoplastic potential. However, reports about their mechanism of action are contradictory, particularly in what concerns the signaling mediators that are involved. Here, the aim was to characterize the effects of orthovanadate in thyroid cancer cells harboring RET/PTC1. MAIN METHODS:Growth behavior of orthovanadate-treated cells was evaluated by the sulphorhodamine B assay, cell cycle analysis and Terminal Transferase dUTP Nick End Labeling (TUNEL). Mitochondrial parameters such as the transmembrane potential and production of reactive oxygen species (ROS) were also assessed. Western blot was used to study cellular signaling. KEY FINDINGS:Low doses of the compound induce a pro-proliferative response. In contrast, treatment with inhibitory concentrations of orthovanadate results in increased phosphorylation of tyrosine 451 of RET/PTC1 and activation of the mTOR/S6R branch of the PI3K/Akt signaling pathway. These concentrations of the drug also induce typical features of apoptosis including DNA fragmentation, loss of mitochondrial membrane potential, production of ROS and activation of caspase-3. Addition of the glial cell line-derived neutrophic factor, a pro-survival stimulator that acts through RET, could not completely block orthovanadate-induced growth inhibition and cell death. SIGNIFICANCE:In this model, orthovanadate induces caspase-dependent apoptosis and interferes with the PI3K/Akt/mTOR cascade. This work provides characterization of the effects of orthovanadate and underlines the possibility of its usefulness as a cell death modulator.

journal_name

Life Sci

journal_title

Life sciences

authors

Gonçalves AP,Videira A,Soares P,Máximo V

doi

10.1016/j.lfs.2011.07.004

subject

Has Abstract

pub_date

2011-09-12 00:00:00

pages

371-7

issue

11-12

eissn

0024-3205

issn

1879-0631

pii

S0024-3205(11)00337-7

journal_volume

pub_type

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Orthovanadate-induced cell death in RET/PTC1-harboring cancer cells involves the activation of caspases and altered signaling through PI3K/Akt/mTOR.