A Ca2+-ATPase Regulates E-cadherin Biogenesis and Epithelial–Mesenchymal Transition in Breast Cancer Cells

Dang, Donna K.; Makena, Monish R.; Llongueras, José P.; Prasad, Hari; Ko, Myungjun; Bandral, Manuj; Rao, Rajini

doi:10.1158/1541-7786.mcr-19-0070

Cited by 27 publications

(48 citation statements)

References 53 publications

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“…It had been demonstrated in vitro that downregulation of E-cadherin is related to the loss of epithelial phenotype (74, 75) and the acquisition of the mesenchymal phenotype, which is associated with invasive behavior; this has been validated using 3D gels and heart explants (76). Further, partial or complete reversal of this process occurs when E-cadherin is constitutively produced (49, 74, 77–79).…”

Section: Cadherins and Tumor Progressionmentioning

confidence: 99%

Cadherin Signaling in Cancer: Its Functions and Role as a Therapeutic Target

et al. 2019

Front. Oncol.

148

118

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Cadherin family includes lists of transmembrane glycoproteins which mediate calcium-dependent cell-cell adhesion. Cadherin-mediated adhesion regulates cell growth and differentiation throughout life. Through the establishment of the cadherin-catenin complex, cadherins provide normal cell-cell adhesion and maintain homeostatic tissue architecture. In the process of cell recognition and adhesion, cadherins act as vital participators. As results, the disruption of cadherin signaling has significant implications on tumor formation and progression. Altered cadherin expression plays a vital role in tumorigenesis, tumor progression, angiogenesis, and tumor immune response. Based on ongoing research into the role of cadherin signaling in malignant tumors, cadherins are now being considered as potential targets for cancer therapies. This review will demonstrate the mechanisms of cadherin involvement in tumor progression, and consider the clinical significance of cadherins as therapeutic targets.

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Section: Cadherins and Tumor Progressionmentioning

confidence: 99%

Cadherin Signaling in Cancer: Its Functions and Role as a Therapeutic Target

et al. 2019

Front. Oncol.

148

118

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“…Calcium is a crucial factor in many key cellular processes [18,19]. In the Wnt/Ca 2+ pathway, frizzled receptors mediate the activation of heterotrimeric G proteins, causing calcium release from the endoplasmic reticulum.…”

Section: Introductionmentioning

confidence: 99%

Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance

Makena

Gatla²,

Verlekar

et al. 2019

IJMS

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103

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Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies. The Wnt/β-catenin pathway controls the maintenance of somatic stem cells in many tissues and organs and is implicated in pancreatic carcinogenesis by regulating cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, tumor immune microenvironment, etc. Further, dysregulated Wnt has been shown to cause drug resistance in pancreatic cancer. Although different Wnt antagonists are effective in pancreatic patients, limitations remain that must be overcome to increase the survival benefits associated with this emerging therapy. In this review, we have summarized the role of Wnt signaling in pancreatic cancer and suggested future directions to enhance the survival of pancreatic cancer patients.

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“…SPCA2 transcript levels are low in triple receptor negative breast cancer derived cell lines [4]. Here, we analyze the TCGA database to show that transcript levels of SPCA2 are significantly (p<0.0001) lower in receptor negative breast tumors compared to receptor positive tumors ( Fig.…”

Section: Low Expression Of Spca2 In Tnbc Correlates With Poor Survivamentioning

confidence: 96%

“…Ectopic expression of SPCA2R was found to diminish mesenchymal gene expression in TNBC cells [4]. Therefore, we evaluated whether concentrations of vorinostat (2.5 µM), shown to induce a modest 3~-fold increase in SPCA2 expression ( Fig.…”

Section: Hdac Inhibitors Promote Met Transition In Tnbc Cellsmentioning

confidence: 99%

Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells

Makena

Dang

et al. 2020

Preprint

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The secretory pathway Ca2+-ATPase SPCA2 is a tumor suppressor in triple receptor negative breast cancer (TNBC), a highly aggressive molecular subtype that lacks tailored treatment options. Low expression of SPCA2 in TNBC confers poor survival prognosis in patients. Previous work has established that re-introducing SPCA2 to TNBC cells restores basal Ca2+ signaling, represses mesenchymal gene expression, mitigates tumor migration in vitro and metastasis in vivo. In this study, we examined the effect of histone deacetylase inhibitors (HDACi) in TNBC cell lines. We show that the pan-HDACi vorinostat and the class I HDACi romidepsin induce dose-dependent upregulation of SPCA2 transcript with concurrent downregulation of mesenchymal markers and tumor cell migration characteristic of epithelial phenotype. Silencing SPCA2 abolished the ability of HDACi to reverse epithelial to mesenchymal transition (EMT). Independent of ATPase activity, SPCA2 elevated resting Ca2+ levels to activate downstream components of non-canonical Wnt/Ca2+ signaling. HDACi treatment led to SPCA2-dependent phosphorylation of CAMKII and β-catenin, turning Wnt signaling off. We conclude that SPCA2 mediates the efficacy of HDACi in reversing EMT in TNBC by a novel mode of non-canonical Wnt/Ca2+ signaling. Our findings provide incentive for screening epigenetic modulators that exploit Ca2+ signaling pathways to reverse EMT in breast tumors.Simple SummaryThe triple receptor negative breast cancer subtype, or TNBC, currently has no tailored treatment options. TNBC is highly metastatic, associated with high patient mortality, and disproportionately occurs in Black/African American women where it contributes to racial disparities in health outcomes. Therefore, we focused on new therapeutic approaches to TNBC. We discovered that levels of the Calcium-ATPase SPCA2 are abnormally low in TNBC and that these low levels correlate with poor survival prognosis in patients. Previously, we showed that recombinant SPCA2 prevented TNBC cells from acquiring aggressive ‘mesenchymal’ properties associated with metastasis both in vitro and in vivo. These findings motivated us to search for drugs that turn the SPCA2 gene back on in TNBC cells. In this study, we show that histone deacetylase inhibitors increase SPCA2 levels, activate Ca2+ signaling and convert cancer cells to a less aggressive ‘epithelial’ state. These findings could lead to new treatment options for TNBC.Graphical Abstract

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A Ca2+-ATPase Regulates E-cadherin Biogenesis and Epithelial–Mesenchymal Transition in Breast Cancer Cells

Cited by 27 publications

References 53 publications

Cadherin Signaling in Cancer: Its Functions and Role as a Therapeutic Target

Cadherin Signaling in Cancer: Its Functions and Role as a Therapeutic Target

Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance

Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells

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