The recent discovery of novel molecular mechanisms of necrosis have raised great interest, as this non-apoptotic pathway might be also employed to circumvent the resistance of cancer cells to conventional, pro-apoptotic therapeutic agents. Programmed necrosis, in particular the tumour necrosis factor (TNF) receptor 1 (TNFR1)-elicited necroptosis was shown to surpass apoptosis. Key role of sphingosine kinase 1 (SphK1) and its product sphingosine-1-phosphate (S1P) had been shown in TNFα signaling via engagement of TNFR1 and the canonical NF-κB activation pathway important in engagement of cancer microenvironment, anti-apoptotic, and metastasis-promoting mechanisms of cancer progression. However, involvement of various S1P receptors in TNFalpha-induced necrosis remains unclear in breast cancer cells. We generated TNFalpha-resistant cells (MCF-7TR) from MCF-7 breast cancer cell line expressing several members of TNF receptor superfamily. We found that level of S1P receptor 3 (S1PR3) was increased in MCF-7TR cells suggesting a possible role of S1PR3 in inhibition of programmed necrosis during cytokine attack. Contrary, level of S1P receptor 2 (S1PR2) was higher in parental TNFalpha-sensitive MCF-7 cells. We further compared the levels of S1PR3 and 2 expressions in three estrogen receptor (ER)-positive cancer cell lines (MCF-7, T47D, and ZR-75-1) and two ER-negative cell lines (MDA-MB-231 and SK-BR-3). Interestingly, the level of S1PR2 expression in highly metastatic MDA-MB-231 and SK-BR-3 cells was very low. S1PR3 was detected at reasonable levels in all tested cells lines. S1PR3 downregulation by specific siRNA increased necrosis-related effects of TNFalpha in four out of five tested cell lines.
|Number of pages
|Published - 13 Feb 2015
|Lorne Cancer 2015: 27th Lorne Cancer Conference - Lorne, Australia
Duration: 12 Feb 2015 → 14 Feb 2015
Conference number: 27th
|Lorne Cancer 2015
|12/02/15 → 14/02/15
|The Lorne Cancer Conference has a long history of delivering a great ambience and vibrancy.
With strong international and national scientific content, it attracts an audience of over 500 delegates representing many of the major hospitals, universities, research institutes and biotechnology companies within Australia.
- S1P receptor 3