Lysophosphatidate Promotes Sphingosine 1-Phosphate Metabolism and Signaling: Implications for Breast Cancer and Doxorubicin Resistance

Abstract Background Overexpressed vascular endothelial growth factor A (VEGFA) and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) cause unrestricted tumor growth and angiogenesis of breast cancer (BRCA), especially triple-negative breast cancer (TNBC). Hence, novel treatment strategy is urgently needed. Results We found sphingosine 1 phosphate receptor 1 (S1PR1) can regulate P-STAT3/VEGFA. Database showed S1PR1 is highly expressed in BRCA and causes the poor prognosis of patients. Interrupting the expression of S1PR1 could inhibit the growth of human breast cancer cells (MCF-7 and MDA-MB-231) and suppress the angiogenesis of human umbilical vein endothelial cells (HUVECs) via affecting S1PR1/P-STAT3/VEGFA axis. Siponimod (BAF312) is a selective antagonist of S1PR1, which inhibits tumor growth and angiogenesis in vitro by downregulating the S1PR1/P-STAT3/VEGFA axis. We prepared pH-sensitive and tumor-targeted shell-core structure nanoparticles, in which hydrophilic PEG2000 modified with the cyclic Arg-Gly-Asp (cRGD) formed the shell, hydrophobic DSPE formed the core, and CaP (calcium and phosphate ions) was adsorbed onto the shell; the nanoparticles were used to deliver BAF312 (BAF312@cRGD-CaP-NPs). The size and potential of the nanoparticles were 109.9 ± 1.002 nm and − 10.6 ± 0.056 mV. The incorporation efficacy for BAF312 was 81.4%. Results confirmed BAF312@cRGD-CaP-NP could dramatically inhibit tumor growth and angiogenesis in vitro and in MDA-MB-231 tumor-bearing mice via downregulating the S1PR1/P-STAT3/VEGFA axis. Conclusions Our data suggest a potent role for BAF312@cRGD-CaP-NPs in treating BRCA, especially TNBC by downregulating the S1PR1/P-STAT3/VEGFA axis. Graphic abstract

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Microfluidic studies of hydrostatic pressure-enhanced doxorubicin resistance in human breast cancer cells

Lab on a Chip ◽

10.1039/d0lc01103g ◽

2021 ◽

Vol 21 (4) ◽

pp. 746-754

Author(s):

Menglin Shang ◽

Su Bin Lim ◽

Kuan Jiang ◽

Yoon Sim Yap ◽

Bee Luan Khoo ◽

...

Keyword(s):

Breast Cancer ◽

Hydrostatic Pressure ◽

Cancer Cells ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Doxorubicin Resistance

Microfluidic studies of hydrostatic pressure-enhanced doxorubicin resistance in human breast cancer cells.

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Application of new multicomponent nanosystems for overcoming doxorubicin resistance in breast cancer therapy

Applied Nanoscience ◽

10.1007/s13204-020-01653-y ◽

2021 ◽

Author(s):

Nataliya Kutsevol ◽

Yuliia Kuziv ◽

Tetiana Bezugla ◽

Pavlo Virych ◽

Andrii Marynin ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Therapy ◽

Breast Cancer Therapy ◽

Doxorubicin Resistance

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ETV7-Mediated DNAJC15 Repression Leads to Doxorubicin Resistance in Breast Cancer Cells

Neoplasia ◽

10.1016/j.neo.2018.06.008 ◽

2018 ◽

Vol 20 (8) ◽

pp. 857-870 ◽

Cited By ~ 5

Author(s):

Federica Alessandrini ◽

Laura Pezzè ◽

Daniel Menendez ◽

Michael A. Resnick ◽

Yari Ciribilli

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Doxorubicin Resistance

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B37 Aberrant sphingosine-1-phosphate metabolism as druggable target in huntington’s disease

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2016-314597.68 ◽

2016 ◽

Vol 87 (Suppl 1) ◽

pp. A22.1-A22

Author(s):

Alba Di Pardo ◽

Enrico Amico ◽

Abdul Basit ◽

Andrea Armirotti ◽

Francesco Scalabrì ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Phosphate Metabolism ◽

Sphingosine 1 Phosphate

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Chitosan-Dextran sulfate coated doxorubicin loaded PLGA-PVA-nanoparticles caused apoptosis in doxorubicin resistance breast cancer cells through induction of DNA damage

Scientific Reports ◽

10.1038/s41598-017-02134-z ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 15

Author(s):

Sumit Siddharth ◽

Anmada Nayak ◽

Deepika Nayak ◽

Birendra Kumar Bindhani ◽

Chanakya Nath Kundu

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Dextran Sulfate ◽

Doxorubicin Resistance

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Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation

Cancers ◽

10.3390/cancers13133357 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3357

Author(s):

Hongmei Zheng ◽

Sumit Siddharth ◽

Sheetal Parida ◽

Xinhong Wu ◽

Dipali Sharma

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Treatment Options ◽

Combined Treatment ◽

High Mobility ◽

Sphingosine 1 Phosphate ◽

Molecular Patterns

Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC.

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