Effects of chemotherapy agents on Sphingosine-1-Phosphate receptors expression in MCF-7 mammary cancer cells.
Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid involved in the regulation of cell proliferation and cancer progression. Increased expression of S1P receptors has been detected in advanced breast tumours with poor prognosis suggesting that S1P receptors might control tumour response to chemotherapy. However, it remains unclear how the levels of S1P receptor expression are influenced by chemotherapy agents. Western immunoblotting, PCR analysis and fluorescent microscopy techniques were used in this study to analyze expression patterns of S1P receptors 2 and 3 (S1P2/S1P3) in MCF-7 breast adenocarcinoma cells treated by Tamoxifen (TAM) and/or Medroxyprogesterone acetate (MPA). We found that TAM/MPA induce downregulation of S1P3 receptors, but stimulate expression of S1P2. According to cell viability and caspase activity analyses, as expected, TAM activated apoptosis. We also detected TAM/MPA-induced autophagy marked by formation of macroautophagosomes and increased level of Beclin 1. Combined application of TAM and MPA resulted in synergistic apoptosis- and autophagy-stimulating effects. Assessed by fluorescent microscopy with autophagosome marker LAMP-2, changes in S1P receptor expression coincided with activation of autophagy, suggestively, directing breast cancer cells towards death. Further studies are warranted to explore the utility of manipulation of S1P2 and S1P3 receptor expression as a novel treatment approach.
Flinders University Department of Surgery & Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford Park, 5042, South Australia, Australia.
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Ghosal
Flinders University Department of Surgery & Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford Park, 5042, South Australia, Australia. Electronic address: olga.sukocheva@flinders.edu.au.
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Sukocheva
Flinders University Department of Surgery & Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford Park, 5042, South Australia, Australia.
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Wang
Flinders University Department of Surgery & Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford Park, 5042, South Australia, Australia.
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Mayne
Flinders University Department of Surgery & Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford Park, 5042, South Australia, Australia.
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Watson
Flinders University Department of Surgery & Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford Park, 5042, South Australia, Australia.
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Hussey
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008525:Medroxyprogesterone / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology
D000970:Antineoplastic Agents; D049349:Receptors, Lysosphingolipid; D013629:Tamoxifen; D008525:Medroxyprogesterone
Autophagy; Mammary cancer; Medroxyprogesterone acetate; Sphingosine-1-phosphate; Tamoxifen