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

被引:0
|
作者
Ganesh Venkatraman
Xiaoyun Tang
Guangwei Du
Amadeo M. Parisentti
Denise G. Hemmings
David N. Brindley
机构
[1] University of Alberta,Department of Biochemistry
[2] University of Alberta,Cancer Research Institute of Northern Alberta
[3] University of Texas Health Science at Houston,Department of Integrative Biology & Pharmacology
[4] Health Sciences North Research Institute,Northern Ontario School of Medicine
[5] University of Alberta,Medical Microbiology and Immunology, Obstetrics and Gynecology, Women and Children’s Health Research Institute, Li Ka Shing Institute of Virology, Cardiovascular Research Center
来源
Cell Biochemistry and Biophysics | 2021年 / 79卷
关键词
Autotaxin; Inflammation; Lipid phosphate phosphatases; Multidrug resistance transporters;
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摘要
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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页码:531 / 545
页数:14
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