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

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Abstract

Lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) promote vasculogenesis, angiogenesis, and wound healing by activating a plethora of overlapping signaling pathways that stimulate mitogenesis, cell survival, and migration. As such, maladaptive signaling by LPA and S1P have major effects in increasing tumor progression and producing poor patient outcomes after chemotherapy and radiotherapy. Many signaling actions of S1P and LPA are not redundant; each are vital in normal physiology and their metabolisms differ. In the present work, we studied how LPA signaling impacts S1P metabolism and signaling in MDA-MB-231 and MCF-7 breast cancer cells. LPA increased sphingosine kinase-1 (SphK1) synthesis and rapidly activated cytosolic SphK1 through association with membranes. Blocking phospholipase D activity attenuated the LPA-induced activation of SphK1 and the synthesis of ABCC1 and ABCG2 transporters that secrete S1P from cells. This effect was magnified in doxorubicin-resistant MCF-7 cells. LPA also facilitated S1P signaling by increasing mRNA expression for S1P1 receptors. Doxorubicin-resistant MCF-7 cells had increased S1P2 and S1P3 receptor expression and show increased LPA-induced SphK1 activation, increased expression of ABCC1, ABCG2 and greater S1P secretion. Thus, LPA itself and LPA-induced S1P signaling counteract doxorubicin-induced death of MCF-7 cells. We conclude from the present and previous studies that LPA promotes S1P metabolism and signaling to coordinately increase tumor growth and metastasis and decrease the effectiveness of chemotherapy and radiotherapy for breast cancer treatment.

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Abbreviations

ATX:

Autotaxin

COX-1,2:

Cyclooxygenase-1,2

DOX:

Doxorubicin

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

LPA:

Lysophosphatidate at physiological pH but often referred to as lysophosphatidic acid

LPA1-6 :

LPA receptors 1-6

LPC:

Lysophosphatidylcholine

LPP:

Lipid phosphate phosphatases

PA:

Phosphatidate

PLD:

Phospholipase D

S1P:

Sphingosine 1-phosphate

S1P1-5 :

S1P receptors 1-5

SPH:

Sphingosine

SphK1:

Sphingosine kinase-1

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Acknowledgements

The research was supported by grants from the Canadian Cancer Society Research Institutes and Canadian Institutes of Health Research to DNB and Natural Sciences and Engineering Research Council of Canada to DGH. A Northern Cancer Foundation (Sudbury) grant to AMP helped support the creation of the MCF-7CC and MCF-7DOX2 cell lines and a grant from the American Heart Association to GD (19TPA34910051) supported the creation of the PA sensors.

Author contributions

G.V. and X.T. (methodology, investigation, and illustrations); G.D. (conceptualization, preparation and characterization of PA sensor); A.M.P. (conceptualization, preparation, and characterization of DOX-resistant MCF-7 cells); D.G.H. (conceptualization, funding acquisition, and writing) and D.N.B. (conceptualization, methodology, funding acquisition, project administration, resources, supervision, and writing). All authors contributed to editing the final version of the paper.

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Authors and Affiliations

  1. Department of Biochemistry, University of Alberta, Edmonton, AB, T6G 2S2, Canada

    Ganesh Venkatraman, Xiaoyun Tang & David N. Brindley

  2. Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, T6G 2S2, Canada

    Xiaoyun Tang, Denise G. Hemmings & David N. Brindley

  3. Department of Integrative Biology & Pharmacology, University of Texas Health Science at Houston, Houston, TX, 77030, USA

    Guangwei Du

  4. Northern Ontario School of Medicine, Health Sciences North Research Institute, Sudbury, ON, P3E 2H2, Canada

    Amadeo M. Parisentti

  5. Medical Microbiology and Immunology, Obstetrics and Gynecology, Women and Children’s Health Research Institute, Li Ka Shing Institute of Virology, Cardiovascular Research Center, University of Alberta, Edmonton, AB, T6G 2S2, Canada

    Denise G. Hemmings

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  1. Ganesh Venkatraman
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Venkatraman, G., Tang, X., Du, G. et al. Lysophosphatidate Promotes Sphingosine 1-Phosphate Metabolism and Signaling: Implications for Breast Cancer and Doxorubicin Resistance. Cell Biochem Biophys 79, 531–545 (2021). https://doi.org/10.1007/s12013-021-01024-6

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