Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer

Fagan-Solis, Katerina D.; Reaves, Denise K.; Rangel, Maria Cristina; Popoff, Michel R.; Stiles, Bradley G.; Fleming, Jodie M.

doi:10.1186/1476-4598-13-163

Cited by 17 publications

(16 citation statements)

References 72 publications

(95 reference statements)

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“…Together with our previous functional studies in breast cancer cell lines (1, 2), the current data support LSR as a novel transcriptional regulator that is responsive to microenvironmental cues. LSR is capable of nuclear localization and DNA binding, and its nuclear functions may be associated with poor patient outcome.…”

Section: Discussionsupporting

confidence: 85%

“…Immunofluorescence was performed with appropriate controls as described (1, 2, 25). Anti-LSR antibodies; Atlas Antibodies and Santa Cruz Biotechnology.…”

Section: Methodsmentioning

confidence: 99%

“…Primary breast epithelial cells, FMEC2, were previously characterized and cultured as described (25, 26). Overexpression vectors were obtained from Origene (Rockville, MD) and cell transfected as described (1, 2). Proliferating cells were treated with Leptomycin B (37nM) one h prior, or 2-bromopalmitate (27-29) (10 and 100μM) 30min prior to treatment, fixation and imaging as described (1, 2, 25).…”

Section: Methodsmentioning

confidence: 99%

“…Cells were lysed in mPer Lysis Buffer (Thermo Scientific, Rockford, IL) supplemented with protease and phosphatase inhibitors (Halt™ Thermo Scientific) then subjected to western analyses as described (1, 2, 25). Antibodies: Atlas Antibodies, LSR; Santa Cruz Biotechnology, LSR, vimentin, GAPDH, Sp3, tubulin; Life Technologies (Grand Island, NY), pSeR; Origene (Rockland, MD), VDAC.…”

Section: Methodsmentioning

confidence: 99%

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Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis

Reaves

Hoadley

Fagan-Solis

et al. 2017

Molecular Cancer Research

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Lipolysis Stimulated Lipoprotein Receptor (LSR) has been found in the plasma membrane and is believed to function in lipoprotein endocytosis and tight junctions. Given the impact of cellular metabolism and junction signaling pathways on tumor phenotypes and patient outcome, it is important to understand how LSR cellular localization mediates its functions. We conducted localization studies, evaluated DNA binding, and examined the effects of nuclear LSR in cells, xenografts, and clinical specimens. We found LSR within the membrane, cytoplasm, and the nucleus of breast cancer cells representing multiple intrinsic subtypes. Chromatin immunoprecipitation (ChIP) showed direct binding of LSR to DNA, and sequence analysis identified putative functional motifs and post-translational modifications of the LSR protein. While neither overexpression of transcript variants, nor pharmacological manipulation of post-translational modification significantly altered localization, inhibition of nuclear export enhanced nuclear localization, suggesting a mechanism for nuclear retention. Co-immunoprecipitation and proximal ligation assays indicated LSR-pericentrin interactions, presenting potential mechanisms for nuclear-localized LSR. The clinical significance of LSR was evaluated using data from over 1,100 primary breast tumors, which showed high LSR levels in basal-like tumors and tumors from African-Americans. In tumors histosections, nuclear localization was significantly associated with poor outcomes. Finally, in vivo xenograft studies revealed that basal-like breast cancer cells that over-express LSR exhibited both membrane and nuclear localization, and developed tumors with 100% penetrance, while control cells lacking LSR developed no tumors. These results show that nuclear LSR alters gene expression and may promote aggressive cancer phenotypes.

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Section: Discussionsupporting

confidence: 85%

“…Immunofluorescence was performed with appropriate controls as described (1, 2, 25). Anti-LSR antibodies; Atlas Antibodies and Santa Cruz Biotechnology.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis

Reaves

Hoadley

Fagan-Solis

et al. 2017

Molecular Cancer Research

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“…CDT is a binary toxin that has an enzymatic subunit, CDTa (47.4 kDa), with ribosyltransferase activity, and a pore-forming delivery subunit, termed CDTb (99 kDa) (15,(19)(20)(21)(22)(23). Prior to cellular entry via endosomes (24)(25)(26)(27), CDT associates with host cell receptor(s), such as the lipolysisstimulated lipoprotein receptor (LSR) and/or CD44 (28)(29)(30)(31). Based on studies with other binary toxins, it was suggested that the low pH in endosomes triggers CDTa translocation into the cytoplasm, via the cell-binding and pore-forming entity, CDTb, but a detailed molecular mechanism for this process remains unknown (32)(33)(34)(35)(36)(37)(38)(39)(40)(41).…”

Section: Introductionmentioning

confidence: 99%

Structure of the cell-binding component of theClostridium difficilebinary toxin reveals a novel macromolecular assembly

Godoy‐Ruiz

Adipietro

et al. 2019

Preprint

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Targeting Clostridium difficile infection (CDI) is challenging because treatment options are limited, and high recurrence rates are common. One reason for this is that hypervirulent CDI often has a binary toxin termed the C. difficile toxin (CDT), in addition to the enterotoxins TsdA and TsdB. CDT has an enzymatic component, termed CDTa, and a pore-forming or delivery subunit termed CDTb. CDTb was characterized here using a combination of single particle cryoEM, X-ray crystallography, NMR, and other biophysical methods. In the absence of CDTa, two novel diheptamer structures for activated CDTb (aCDTb; 1.0 MDa) were solved at atomic resolution including a symmetric ( Sym CDTb; 3.14 Å) and an asymmetric form ( Asym CDTb; 2.84 Å). Roles played by two receptor-binding domains of aCDTb were of particular interest since RBD1 lacks sequence homology to any other known toxin, and the RBD2 domain is completely absent in other well-studied heptameric toxins (i.e. anthrax). For Asym CDTb, a novel Ca 2+ binding site was discovered in RBD1 that is important for its stability, and RBD2 was found to be critical for host cell toxicity and the novel diheptamer fold for both forms of aCDTb. Together, these studies represent a starting point for structure-based drug-discovery strategies to targeting CDT in the most severe strains of CDI. SIGNIFICANCE STATEMENT:There is a high burden from C. difficile infection (CDI) throughout the world, and the Center for Disease Control (CDC) reports more than 500,000 cases annually in the United States, resulting in an estimated 15,000 deaths. In addition to the large clostridial toxins, TcdA/TcdB, a third C. difficile binary toxin (CDT) is associated with the most serious outbreaks of drug resistant CDI in the 21 st century. Here, structural biology and biophysical approaches were used to characterize the cell binding component of CDT, termed CDTb, at atomic resolution. Surprisingly, two novel structures were solved from a single sample that help to explain the molecular underpinnings of C. difficile toxicity. These structures will also be important for targeting this human pathogen via structure-based therapeutic design methods. INTRODUCTION:

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Potentiation of cancerous progression by LISCH7 via direct stimulation of TGFB1 transcription in triple‐negative breast cancer

Tang

Zhou

Liu

et al. 2020

J of Cellular Biochemistry

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As an aggressive breast cancer (BCa) subtype, triple‐negative breast cancer (TNBC) responses poorly to chemotherapy and endocrine therapy, and usually has a worse prognosis. This is largely due to the lack of specific therapeutic targets, laying claim to an imperious demand to clarify the key signaling pathways potentiating TNBC progression. Herein, we report that expression levels of the liver‐specific bHLH‐Zip transcription factor (LISCH7), a recently identified key player in cancerous progression, preferentially enriched in TNBC in comparison with other BCa subtypes, and this upregulation was observed to be correlated to a poor survival outcome in patients with TNBC. Ablation of LISCH7 in TNBC cells impaired cell proliferation, reduced cell invasiveness, and enhanced sensitivity to the first‐line chemotherapeutic drug docetaxel at both in vitro and in vivo levels. Importantly, concurrent induction of TGFB1, the gene encoding transforming growth factor‐β1 (TGF‐β1), an essential multipluripotent regulator of TNBC, was accompanied with these alterations in cancerous properties. We further showed that LISCH7 could directly bind to the TGFB1 promoter and stimulate TGFB1 transcription in TNBC cells. The recruitment of LISCH7 onto the TGFB1 chromatin and transactivation of TGFB1 were substantially augmented by treatment with the exogenous TGF‐β1 in a time‐ and dose‐dependent manner. Collectively, these findings suggest that LISCH7 and TGF‐β1 form a reciprocal positive regulatory loop and cooperatively regulate cancerous progression in TNBC cells. Thus, simultaneous inhibition of both LISCH7 and TGF‐β1 signaling may represent a more effective approach to counteract advanced TNBC.

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Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer

Cited by 17 publications

References 72 publications

Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis

Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis

Structure of the cell-binding component of theClostridium difficilebinary toxin reveals a novel macromolecular assembly

Potentiation of cancerous progression by LISCH7 via direct stimulation of TGFB1 transcription in triple‐negative breast cancer

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