A Genome-Wide Loss-of-Function Screen Identifies SLC26A2 as a Novel Mediator of TRAIL Resistance

Dimberg, Lina Y.; Towers, Christina G.; Behbakht, Kian; Hotz, Taylor; Kim, Jihye; Fosmire, Susan; Porter, Christopher C.; Tan, Aik Choon; Thorburn, Andrew; Ford, Heide L.

doi:10.1158/1541-7786.mcr-16-0234

Cited by 11 publications

(6 citation statements)

References 49 publications

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“…Lines of evidence have revealed potential roles of SLC26A2 in the pathogenesis of primary aldosteronism and development of ulcerative colitis and Crohn's disease and colon cancer, and even dtd mice showed abnormal aldosterone secretion, thereby justifying its ubiquitous non-skeletal expression [ [57] , [58] , [59] , [60] , [61] ]. Importantly, SLC26A2 is also expressed in cytotrophoblasts and considered to facilitate maternal-to-fetal delivery of sulfate [ 62 , 63 ].…”

Section: Resultsmentioning

confidence: 99%

Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias

Zheng

Lin

et al. 2019

EBioMedicine

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BackgroundMutations in the SLC26A2 gene cause a spectrum of currently incurable human chondrodysplasias. However, genotype-phenotype relationships of SLC26A2-deficient chondrodysplasias are still perplexing and thus stunt therapeutic development.MethodsTo investigate the causative role of SLC26A2 deficiency in chondrodysplasias and confirm its skeleton-specific pathology, we generated and analyzed slc26a2−/− and Col2a1-Cre; slc26a2fl/fl mice. The therapeutic effect of NVP-BGJ398, an FGFR inhibitor, was tested with both explant cultures and timed pregnant females.FindingsTwo lethal forms of human SLC26A2-related chondrodysplasias, achondrogenesis type IB (ACG1B) and atelosteogenesis type II (AO2), are phenocopied by slc26a2−/− mice. Unexpectedly, slc26a2−/− chondrocytes are defective for collagen secretion, exhibiting intracellular retention and compromised extracellular deposition of ColII and ColIX. As a consequence, the ATF6 arm of the unfolded protein response (UPR) is preferentially triggered to overactivate FGFR3 signaling by inducing excessive FGFR3 in slc26a2−/− chondrocytes. Consistently, suppressing FGFR3 signaling by blocking either FGFR3 or phosphorylation of the downstream effector favors the recovery of slc26a2−/− cartilage cultures from impaired growth and unbalanced cell proliferation and apoptosis. Moreover, administration of an FGFR inhibitor to pregnant females shows therapeutic effects on pathological features in slc26a2−/− newborns. Finally, we confirm the skeleton-specific lethality and pathology of global SLC26A2 deletion through analyzing the Col2a1-Cre; slc26a2fl/fl mouse line.InterpretationOur study unveils a previously unrecognized pathogenic mechanism underlying ACG1B and AO2, and supports suppression of FGFR3 signaling as a promising therapeutic approach for SLC26A2-related chondrodysplasias.FundThis work was supported by National Natural Science Foundation of China (81871743, 81730065 and 81772377).

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Section: Resultsmentioning

confidence: 99%

Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias

Zheng

Lin

et al. 2019

EBioMedicine

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“…Our finding that vanadiumcontaining compounds selectively kill cancer cells expressing high levels of the sulfate transporter SLC26A2 was also surprising, given that a mechanistic link between the two had not been previously suspected. A recent study showed that SLC26A2 expression is a mechanism of resistance to TNF-related apoptosis-inducing ligandinduced cell death 38 ; it remains to be determined whether that mechanism is relevant to vanadium-induced killing and whether these compounds dysregulate sulfate homeostasis. Perhaps most interesting was our observation that the drug tepoxalin has the unique ability to inhibit cells that express high levels of the multidrug resistance gene ABCB1.…”

Section: Discussionmentioning

confidence: 99%

Discovering the anticancer potential of non-oncology drugs by systematic viability profiling

et al. 2020

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Anticancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth-inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. We used PRISM (profiling relative inhibition simultaneously in mixtures), a molecular barcoding method, to screen drugs against cell lines in pools. An unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines in a manner predictable from the molecular features of the cell lines. Our findings include compounds that killed by inducing phosphodiesterase 3A-Schlafen 12 complex formation, vanadium-containing compounds whose killing depended on the sulfate transporter SLC26A2, the alcohol dependence drug disulfiram, which killed cells with low expression of metallothioneins, and the anti-inflammatory drug tepoxalin, which killed via the multidrug resistance protein ATP-binding cassette subfamily B member 1 (ABCB1). The PRISM drug repurposing resource (https://depmap.org/repurposing) is a starting point to develop new oncology therapeutics, and more rarely, for potential direct clinical translation. NATURE CANCER | VOL 1 | FeBRUARY 2020 | 235-248 | www.nature.com/natcancer 235 ResouRce NATuRE CANCER the remaining compounds being either chemotherapeutics (2%) or targeted oncology agents (21%).Screening results. We employed a 2-stage screening strategy whereby drugs were first screened in triplicate at a single dose (2.5 µM); 1,448 drugs screening positives were then rescreened in triplicate in an eight-point dose-response ranging from 10 µM to 610 pM ( Fig. 1c and Supplementary Table 2). Interestingly, most active compounds (774 out of 1,448, 53%) were originally developed for non-oncology clinical indications (Fig. 1d). The primary and secondary screening datasets are available on the Cancer Dependency Map portal (https://depmap.org/repurposing) and figshare (https://doi.org/10.6084/m9.figshare.9393293; Extended Data Figs. 1-4). We compared the PRISM results to two gold standard datasets: GDSC (ref. 2 ) and CTD 2 (ref. 3 ). The three datasets shared 84 compounds tested on a median of 236 common cell lines, yielding 16,650 shared data points. The PRISM dataset had a similar degree of concordance to GDSC and CTD 2 (Pearson correlations of 0.60 and 0.61, respectively over all shared data points), as the GDSC and CTD 2 datasets had to each other (Pearson correlation 0.62) (Extended Data Fig. 5a). The three datasets remained similarly concordant when the analysis was restricted to data points showing evidence of anticancer activity (Extended Data Fig. 5b). We conclude that, despite differences in assay format, sources of compounds 5 and sources of cell lines 6 , the PRISM Repurposing dataset is similarly robust compared to existing pharmacogenomic datasets.At the level of individual compound dose-responses, we note that the PRISM Repurposing dataset tends to be somewhat noisier, with a higher standard error estimated from vehicle contr...

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“…3.10. Col2a1-Cre; slc26a2 fl/fl mice recapitulate the phenotype of slc26a2 −/− mice Lines of evidence have revealed potential roles of SLC26A2 in the pathogenesis of primary aldosteronism and development of ulcerative colitis and Crohn's disease and colon cancer, and even dtd mice showed abnormal aldosterone secretion, thereby justifying its ubiquitous nonskeletal expression [57][58][59][60][61]. Importantly, SLC26A2 is also expressed in cytotrophoblasts and considered to facilitate maternal-to-fetal delivery of sulfate [62,63].…”

Section: Targeting Fgfr3 Signaling Modulates Cartilage Growth In Vitromentioning

confidence: 98%

Suppressing UPR-Dependent Overactivation of FGFR3 Signaling Ameliorates SLC26A2-Deficient Chondrodysplasias

Chen¹,

Lin²,

Xu³

et al. 2018

SSRN Journal

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Background: Mutations in the SLC26A2 gene cause a spectrum of currently incurable human chondrodysplasias. However, genotype-phenotype relationships of SLC26A2-deficient chondrodysplasias are still perplexing and thus stunt therapeutic development. Methods: To investigate the causative role of SLC26A2 deficiency in chondrodysplasias and confirm its skeletonspecific pathology, we generated and analyzed slc26a2 −/− and Col2a1-Cre; slc26a2 fl/fl mice. The therapeutic effect of NVP-BGJ398, an FGFR inhibitor, was tested with both explant cultures and timed pregnant females. Findings: Two lethal forms of human SLC26A2-related chondrodysplasias, achondrogenesis type IB (ACG1B) and atelosteogenesis type II (AO2), are phenocopied by slc26a2 −/− mice. Unexpectedly, slc26a2 −/− chondrocytes are defective for collagen secretion, exhibiting intracellular retention and compromised extracellular deposition of ColII and ColIX. As a consequence, the ATF6 arm of the unfolded protein response (UPR) is preferentially triggered to overactivate FGFR3 signaling by inducing excessive FGFR3 in slc26a2 −/− chondrocytes. Consistently, suppressing FGFR3 signaling by blocking either FGFR3 or phosphorylation of the downstream effector favors the recovery of slc26a2 −/− cartilage cultures from impaired growth and unbalanced cell proliferation and apoptosis. Moreover, administration of an FGFR inhibitor to pregnant females shows therapeutic effects on pathological features in slc26a2 −/− newborns. Finally, we confirm the skeleton-specific lethality and pathology of global SLC26A2 deletion through analyzing the Col2a1-Cre; slc26a2 fl/fl mouse line. Interpretation: Our study unveils a previously unrecognized pathogenic mechanism underlying ACG1B and AO2, and supports suppression of FGFR3 signaling as a promising therapeutic approach for SLC26A2-related chondrodysplasias.

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A Genome-Wide Loss-of-Function Screen Identifies SLC26A2 as a Novel Mediator of TRAIL Resistance

Cited by 11 publications

References 49 publications

Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias

Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias

Discovering the anticancer potential of non-oncology drugs by systematic viability profiling

Suppressing UPR-Dependent Overactivation of FGFR3 Signaling Ameliorates SLC26A2-Deficient Chondrodysplasias

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