Pharmacological inhibition of sphingosine kinase isoforms alters estrogen receptor signaling in human breast cancer

Antoon, James W.; Meacham, William D.; Bratton, Melyssa R.; Slaughter, Evelyn M.; Rhodes, Lyndsay V.; Ashe, Hasina; Wiese, Thomas E.; Burow, Matthew E.; Beckman, Barbara S.

doi:10.1530/jme-10-0116

Cited by 45 publications

(64 citation statements)

References 46 publications

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“…Numerous studies have shown the inhibitors of SphK1 decrease cancer cell growth and survival and also sensitize them to chemotherapeutics. For example, the non-selective SphK1/2 inhibitor, SKI-II, has been shown to abrogate ERa signaling, likely acting both as a SphK inhibitor and in a similar manner as tamoxifen by directly binding to the ERa and blocking binding of E 2 (Antoon et al, 2011a). Moreover, SphK1 inhibition by siRNA knockdown or treatment with SKI-5C sensitizes TNBC cells to chemotherapeutic drugs (Datta et al, 2014).…”

Section: Inhibition Of the Er/s1p Axismentioning

confidence: 99%

Sphingosine-1-phosphate and estrogen signaling in breast cancer

Maczis

Milstien

Spiegel

2016

Advances in Biological Regulation

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Breast cancer remains the most common malignant disease in women. The estrogen receptor-α (ERα) and its ligand 17β-estradiol (E2) play important roles in breast cancer. E2 elicits cellular effects by binding to ERα in the cytosol followed by receptor dimerization and translocation to the nucleus where it regulates gene expression by binding to ERE response elements. However, it has become apparent that E2 also exerts rapid non-genomic effects through membrane-associated receptors. There is emerging evidence that this induces formation of the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P). S1P in turn has been implicated in many processes important in breast cancer progression. One of the enzymes that produce S1P, sphingosine kinase 1 (SphK1), is upregulated in breast cancer and its expression has been correlated with poor prognosis. This review is focused on the role of the SphK/S1P axis in estrogen signaling and breast cancer progression and will discuss new therapeutic approaches targeting this axis for breast cancer treatment.

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Section: Inhibition Of the Er/s1p Axismentioning

confidence: 99%

Sphingosine-1-phosphate and estrogen signaling in breast cancer

Maczis

Milstien

Spiegel

2016

Advances in Biological Regulation

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“…91 Further, there was a report that a SphK1-selective inhibitor (SKI-II) abrogated ER signaling, possibly through direct binding to the ER similar to tamoxifen, diminished viability and proliferation of breast carcinoma cells without similar effects on normal breast epithelial cells. 92 Additionally, high levels of S1P 1 and S1P 3 expression in ER-positive breast cancer patients are also reported to be correlated with poor prognosis as well. 91 There have been several reports on the effect of a Sphk2-selective inhibitor ABC294640 on breast cancer that it altered ER signaling in MCF-7 cells, 93 induced apoptosis through the intrinsic pathway, 94 and decreased chemo-resistant breast cancer tumor growth in vivo.…”

Section: S1p and Breast Cancermentioning

confidence: 99%

The Role of Sphingosine-1-Phosphate in Breast Cancer Tumor-Induced Lymphangiogenesis

Aoyagi

Nagahashi

Yamada

et al. 2012

Lymphatic Research and Biology

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Sphingosine-1-phosphate (S1P) is a potent sphingolipid metabolite that regulates a number of biological processes critical for cancer. S1P produced inside cancer cells is exported and exerts its extracellular functions by binding to its specific receptors in an autocrine, paracrine, and/or endocrine manner, which is known as insideout signaling. S1P is also known to exert its intracellular functions especially in the inflammatory process, but its relevance to cancer biology remains to be elucidated. Recently, there have been growing interests in the role of S1P in breast cancer progression, including angiogenesis and lymphangiogenesis. Our group demonstrated that activation of sphingosine kinase 1, the enzyme that catalyzes the phosphorylation of sphingosine to S1P, is a key step of this process. In this review, we will cover our current knowledge on the role of S1P signaling pathway in breast cancer progression with an emphasis on its role in tumor-induced lymphangiogenesis. Lymph Node Metastasis Is a Major Prognostic Predictor in Breast CancerB reast cancer first metastasizes to its sentinel lymph node, and the level of lymph node metastasis is one of the three factors used for clinical staging of this disease (TNM Staging), thus it is a major prognostic predictor of clinical outcome.1 A breast cancer's metastatic potential is determined by complex and specific genetic gains and/or losses of function that enable cancer cells to proliferate, migrate out from their primary site to invade into the blood or lymphatic vasculature in the host, thereby providing tumor cells an access/ conduit to metastasize. The mechanism of tumor-induced lymphangiogenesis, generation of new lymphatic vessels from the host induced by the tumor, is relatively understudied despite the fact that ample clinical and experimental evidence suggests that lymphangiogenesis provides a gateway to systemic metastasis. [2][3][4] Understanding the molecular mechanisms regulating this process is expected to have significant impact on the understanding of cancer biology and potentially lead to the development of new treatment strategies.

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“…In the past decade, SK1 has been found to have tumorigenic effects in breast cancer, specifically in promoting the growth and estrogen responsiveness of breast cancer cells (15)(16)(17). SK1 acts as an estrogen signaling regulator in breast cancer (18), coupling hormone receptor action with downstream functional actuators (19). Not only is SK1 involved in enhancing breast cancer cell proliferation, recent evidence suggests that endocrine resistance is causally associated with the overexpression of SK1 (20) and that the mechanism may be an overreliance on aberrant SK1 signaling.…”

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confidence: 99%

Sphingosine Kinase 1 Isoform-Specific Interactions in Breast Cancer

Yagoub

Wilkins

Lay

et al. 2014

Molecular Endocrinology

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Sphingosine kinase 1 (SK1) is a signaling enzyme that catalyzes the formation of sphingosine-1-phosphate. Overexpression of SK1 is causally associated with breast cancer progression and resistance to therapy. SK1 inhibitors are currently being investigated as promising breast cancer therapies. Two major transcriptional isoforms, SK143 kDa and SK151 kDa, have been identified; however, the 51 kDa variant is predominant in breast cancer cells. No studies have investigated the protein-protein interactions of the 51 kDa isoform and whether the two SK1 isoforms differ significantly in their interactions. Seeking an understanding of the regulation and role of SK1, we used a triple-labeling stable isotope labeling by amino acids in cell culture-based approach to identify SK1-interacting proteins common and unique to both isoforms. Of approximately 850 quantified proteins in SK1 immunoprecipitates, a high-confidence list of 30 protein interactions with each SK1 isoform was generated via a meta-analysis of multiple experimental replicates. Many of the novel identified SK1 interaction partners such as supervillin, drebrin, and the myristoylated alanine-rich C-kinase substrate-related protein supported and highlighted previously implicated roles of SK1 in breast cancer cell migration, adhesion, and cytoskeletal remodeling. Of these interactions, several were found to be exclusive to the 43 kDa isoform of SK1, including the protein phosphatase 2A, a previously identified SK1-interacting protein. Other proteins such as allograft inflammatory factor 1-like protein, the latent-transforming growth factor β-binding protein, and dipeptidyl peptidase 2 were found to associate exclusively with the 51 kDa isoform of SK1. In this report, we have identified common and isoform-specific SK1-interacting partners that provide insight into the molecular mechanisms that drive SK1-mediated oncogenicity.

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Pharmacological inhibition of sphingosine kinase isoforms alters estrogen receptor signaling in human breast cancer

Cited by 45 publications

References 46 publications

Sphingosine-1-phosphate and estrogen signaling in breast cancer

Sphingosine-1-phosphate and estrogen signaling in breast cancer

The Role of Sphingosine-1-Phosphate in Breast Cancer Tumor-Induced Lymphangiogenesis

Sphingosine Kinase 1 Isoform-Specific Interactions in Breast Cancer

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