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SDF-1 chemokine signalling modulates the apoptotic responses to iron deprivation of clathrin-depleted DT40 cells.

ABSTRACT: We have previously deleted both endogenous copies of the clathrin heavy-chain gene in the chicken pre B-cell-line DT40 and replaced them with clathrin under the control of a tetracycline-regulatable promoter (Tet-Off). The originally derived cell-line DKO-S underwent apoptosis when clathrin expression was repressed. We have also described a cell-line DKO-R derived from DKO-S cells that was less sensitive to clathrin-depletion. Here we show that the restriction of transferrin uptake, resulting in iron deprivation, is responsible for the lethal consequence of clathrin-depletion. We further show that the DKO-R cells have up-regulated an anti-apoptotic survival pathway based on the chemokine SDF-1 and its receptor CXCR4. Our work clarifies several puzzling features of clathrin-depleted DT40 cells and reveals an example of how SDF-1/CXCR4 signalling can abrogate pro-apoptotic pathways and increase cell survival. We propose that the phenomenon described here has implications for the therapeutic approach to a variety of cancers.

SUBMITTER: Pance A

PROVIDER: S-EPMC4146602 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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SDF-1 chemokine signalling modulates the apoptotic responses to iron deprivation of clathrin-depleted DT40 cells.

Pance Alena A Morrissey-Wettey Frank R FR Craig Helen H Downing Alison A Talbot Richard R Jackson Antony P AP

PloS one 20140827 8

We have previously deleted both endogenous copies of the clathrin heavy-chain gene in the chicken pre B-cell-line DT40 and replaced them with clathrin under the control of a tetracycline-regulatable promoter (Tet-Off). The originally derived cell-line DKO-S underwent apoptosis when clathrin expression was repressed. We have also described a cell-line DKO-R derived from DKO-S cells that was less sensitive to clathrin-depletion. Here we show that the restriction of transferrin uptake, resulting in ...[more]

PMID: 25162584

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Project description:The activation of dioxygen is the keystone of all forms of aerobic life. Many biological functions rely on the redox versatility of metal ions to perform reductive activation-mediated processes entailing dioxygen and its partially reduced species including superoxide, hydrogen peroxide, and hydroxyl radicals, also known as reactive oxygen species (ROS). In biomimetic chemistry, a number of synthetic approaches have sought to design, synthesize and characterize reactive intermediates such as the metal-superoxo, -peroxo, and -oxo species, which are commonly found as key intermediates in the enzymatic catalytic cycle. However, the use of these designed complexes and their corresponding intermediates as potential candidates for cancer therapeutics has scarcely been endeavored. In this context, a series of biomimetic first-row transition metal complexes bearing a picolylamine-based water-soluble ligand, [M(HN3O2)]2+ (M = Mn2+, Fe2+, Co2+, Cu2+; HN3O2 = 2-(2-(bis(pyridin-2-ylmethyl)amino)ethoxy)ethanol) were synthesized and characterized by various spectroscopic methods including X-ray crystallography and their dioxygen and ROS activation reactivity were evaluated in situ and in vitro. It turned out that among these metal complexes, the iron complex, [Fe(HN3O2)(H2O)]2+, was capable of activating dioxygen and hydrogen peroxide and produced the ROS species (e.g., hydroxyl radical). Upon the incubation of these complexes with different cancer cells, such as cervical, breast, and colorectal cancer cells (MDA-MB-231, AU565, SK-BR-3, HeLa S3, HT-29, and HCT116 cells), only the iron complex triggered cellular apoptosis specifically for colorectal cancer cells; the other metal complexes show negligible anti-proliferative activity. More importantly, the biomimetic complexes were harmless to normal cells and produced less ROS therein. The use of immunocytochemistry combined with western blot analysis strongly supported that apoptosis occurred via the intrinsic mitochondrial pathway; in the intracellular network, [Fe(HN3O2)(H2O)]2+ resulted in (i) the activation and/or production of ROS species, (ii) the induction of intracellular impaired redox balance, and (iii) the promotion of the mitochondrial apoptotic signaling pathway in colorectal cancer cells. The results have implications for developing novel biomimetic complexes in cancer treatments and for designing potent candidates with cancer-specific antitumor activity.

Dataset Information

SDF-1 chemokine signalling modulates the apoptotic responses to iron deprivation of clathrin-depleted DT40 cells.

Publications

SDF-1 chemokine signalling modulates the apoptotic responses to iron deprivation of clathrin-depleted DT40 cells.

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