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||1|
|Publication status||Published - 13 Feb 2015|
|Event||Lorne Cancer 2015: 27th Lorne Cancer Conference - Lorne, Australia|
Duration: 12 Feb 2015 → 14 Feb 2015
Conference number: 27th
|Conference||Lorne Cancer 2015|
|Period||12/02/15 → 14/02/15|
|Other||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