Phosphate dysregulation via the XPR1:KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer

2020 ◽  
Author(s):  
Daniel P Bondeson ◽  
Brenton R Paolella ◽  
Adhana Asfaw ◽  
Michael Rothberg ◽  
Thomas Skipper ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Uterine Cancer ◽  
Cancer Cell Lines ◽  
Loss Of Function ◽  
Human Cancer Cell Lines

Clinical outcomes for patients with ovarian and uterine cancers have not improved greatly in the past twenty years. To identify ovarian and uterine cancer vulnerabilities, we analyzed genome-scale CRISPR/ Cas9 loss-of-function screens across 739 human cancer cell lines. We found that many ovarian cancer cell lines overexpress the phosphate importer SLC34A2, which renders them sensitive to loss of the phosphate exporter XPR1. We extensively validated the XPR1 vulnerability in cancer cell lines and found that the XPR1 dependency was retained in vivo. Overexpression of SLC34A2 is frequently observed in tumor samples and is regulated by PAX8 - a transcription factor required for ovarian cancer survival. XPR1 overexpression and copy number amplifications are also frequently observed. Mechanistically, SLC34A2 overexpression and impaired phosphate efflux leads to the accumulation of intracellular phosphate and cell death. We further show that proper localization and phosphate efflux by XPR1 requires a novel binding partner, KIDINS220. Loss of either XPR1 or KIDINS220 results in acidic vacuolar structures which precede cell death. These data point to the XPR1:KIDINS220 complex - and phosphate dysregulation more broadly - as a therapeutic vulnerability in ovarian cancer.

Ectopic expression of Flt3 kinase inhibits proliferation and promotes cell death in different human cancer cell lines

2012 ◽  
Vol 28 (4) ◽  
pp. 201-212 ◽  
Author(s):  
Eystein Oveland ◽  
Line Wergeland ◽  
Randi Hovland ◽  
James B. Lorens ◽  
Bjørn Tore Gjertsen ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Ectopic Expression ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines

scholarly journals A putative PPAR beta/delta agonist induces cell death in human cancer cell lines

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
David Kelly Strom ◽  
Dalon Li ◽  
Hanna Brinkman ◽  
Stephanie Gleason ◽  
Sarah Hershberger ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines

scholarly journals The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis

2016 ◽  
Vol 241 (18) ◽  
pp. 2015-2022 ◽  
Author(s):  
Mohamed El-Mesery ◽  
Mohamed E Shaker ◽  
Abdelaziz Elgaml
Keyword(s):  
Cell Death ◽  
Immune System ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Tnf Α ◽  
Smac Mimetic

The inhibitors of apoptosis proteins are implicated in promoting cancer cells survival and resistance toward immune surveillance and chemotherapy. Second mitochondria-derived activator of caspases (SMAC) mimetics are novel compounds developed to mimic the inhibitory effect of the endogenous SMAC/DIABLO on these IAPs. Here, we examined the potential effects of the novel SMAC mimetic BV6 on different human cancer cell lines. Our results indicated that BV6 was able to induce cell death in different human cancer cell lines. Mechanistically, BV6 dose dependently induced degradation of IAPs, including cIAP1 and cIAP2. This was coincided with activating the non-canonical NF -kappa B (NF-κB) pathway, as indicated by stabilizing NF-κB-inducing kinase (NIK) for p100 processing to p52. More interestingly, BV6 was able to sensitize some of the resistant cancer cell lines to apoptosis induced by the death ligands tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) that are produced by different cells of the immune system. Such cell death enhancement was mediated by inducing an additional cleavage of caspase-9 to augment that of caspase-8 induced by death ligands. This eventually led to more processing of the executioner caspase-3 and poly (ADP-ribose) polymerase (PARP). In conclusion, therapeutic targeting of IAPs by BV6 might be an effective approach to enhance cancer regression induced by immune system. Our data also open up the future possibility of using BV6 in combination with other antitumor therapies to overcome cancer drug resistance.

scholarly journals Potential of four marine-derived fungi extracts as anti-proliferative and cell death-inducing agents in seven human cancer cell lines

2015 ◽  
Vol 8 (10) ◽  
pp. 798-806 ◽  
Author(s):  
Alice Abreu Ramos ◽  
Maria Prata-Sena ◽  
Bruno Castro-Carvalho ◽  
Tida Dethoup ◽  
Suradet Buttachon ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines

scholarly journals Anticancer Activity of Ag(I) N-Heterocyclic Carbene Complexes Derived from 4,5-Dichloro-1H-Imidazole

2008 ◽  
Vol 2008 ◽  
pp. 1-7 ◽  
Author(s):  
Doug A. Medvetz ◽  
Khadijah M. Hindi ◽  
Matthew J. Panzner ◽  
Andrew J. Ditto ◽  
Yang H. Yun ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Silver Complexes ◽  
Carbene Complexes ◽  
Human Cancer Cell Lines

A class of Ag(I) N-heterocyclic carbene silver complexes, 1–3, derived from 4,5-dichloro-1H-imidazole has been evaluated for their anticancer activity against the human cancer cell lines OVCAR-3 (ovarian), MB157 (breast), and Hela (cervical). Silver complexes 1–3 are active against the ovarian and breast cancer cell lines. A preliminary in vivo study shows 1 to be active against ovarian cancer in mice. The results obtained in these studies warrant further investigation of these compounds in vivo.

scholarly journals Identification and Characterization of Separase Inhibitors (Sepins) for Cancer Therapy

2014 ◽  
Vol 19 (6) ◽  
pp. 878-889 ◽  
Author(s):  
Nenggang Zhang ◽  
Kathleen Scorsone ◽  
Gouqing Ge ◽  
Caterina C. Kaffes ◽  
Lacey E. Dobrolecki ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Lines ◽  
Cancer Cell ◽  
Small Molecule ◽  
High Throughput Screening ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell Lines ◽  
Small Molecule Compound

Separase is an endopeptidase that cleaves cohesin subunit Rad21, facilitating the repair of DNA damage during interphase and the resolution of sister chromatid cohesion at anaphase. Separase activity is negatively regulated by securin and Cdk1–cyclin B in vivo. Separase overexpression is reported in a broad range of human tumors, and its overexpression in mouse models results in tumorigenesis. To elucidate further the mechanism of separase function and to test if inhibition of overexpressed separase can be used as a strategy to inhibit tumor-cell proliferation, small-molecule inhibitors of separase enzyme are essential. Here, we report a high-throughput screening for separase inhibitors (Sepins). We developed a fluorogenic separase assay using rhodamine 110–conjugated Rad21 peptide as substrate and screened a small-molecule compound library. We identified a noncompetitive inhibitor of separase called Sepin-1 that inhibits separase enzymatic activity with a half maximal inhibitory concentration (IC50) of 14.8 µM. Sepin-1 can inhibit the growth of human cancer cell lines and breast cancer xenograft tumors in mice by inhibiting cell proliferation and inducing apoptosis. The sensitivity to Sepin-1 in most cases is positively correlated to the level of separase in both cancer cell lines and tumors.

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