Prolactin upregulates sphingosine kinase-1 expression and activity in the human breast cancer cell line MCF7 and triggers enhanced proliferation and migration

Abstract

Sphingosine kinases (SK) catalyze the formation of sphingosine-1-phosphate (S1P) which plays a crucial role in cell growth and survival. Here, we show that prolactin (PRL) biphasically activates the SK-1, but not the SK-2 subtype, in the breast adenocarcinoma cell-line MCF7. A first peak occurs after minutes of stimulation and is followed by a second delayed activation after hours of stimulation. A similar biphasic effect on SK-1 activity is seen for 17b-estradiol (E 2 ). The delayed activation of SK-1 derives from an upregulated mRNA and protein expression and is due to increased SK-1 promoter activity and mechanistically involves STAT5 activation as well as protein kinase C and the classical mitogen-activated protein kinases. Furthermore, glucocorticoids also block both hormone-induced SK-1 expression and activity. Functionally, long-term stimulation of MCF7 cells with PRL or E 2 is well known to trigger increased cell proliferation and migration. Both hormone-induced cell responses critically involve SK-1 activation since the depletion of SK-1, but not SK-2, by siRNA transfection abolishes the hormone-induced cell proliferation and migration. In summary, our data show that PRL and E 2 cause a pronounced delayed SK-1 activation which is due to increased gene transcription, and critically determines the capability of cells to grow and move. Thus, the SK-1 may represent a novel attractive target for anti-tumor therapy.

Role of sphingolipids in oestrogen signalling in breast cancer cells: an update

“…Hypothetically, it might work within a similar scheme shown for phytoestrogen signalling in MCF-7 cells. Supporting this both, GPR30 and ERa were involved in oestrogen-dependent activation of SphK1 (Sukocheva et al 2003, Doll et al 2007). The exact mechanisms underlying rapid (15-30 min) SphK1 activation by E 2 also remain elusive, leaving the possibility of direct or adaptormediated interactions between ERa, GPR30 and SphK1 still unexplored.…”

“…There is strong evidence demonstrating that SphK1 has an important growth-regulatory role in BCC (Doll et al 2007, Rosen & Goetzl 2005, Sukocheva et al 2006. Other authors (Doll et al 2007) and we (Sukocheva et al 2003) have demonstrated that in BCC the proliferation-stimulating steroid hormone oestrogen activates the SphK1 (Fig.…”

“…Prolonged activation of SphK1 by oestrogen is associated with ER-regulated genomic signalling and might indicate induction of the SPHK1 promoter via engagement of the oestrogen response element (Doll et al 2007). Several potential transcription factor binding sites have been identified in the SPHK promoter region, including Sp1, AP1, AP2, AP4 and STAT (Nakade et al 2003, Sobue et al 2005.…”

Neuroendocrine influences on cancer biology

“…Prolactin plays a functional role in tumor cell proliferation and promotes survival of breast, prostate, endometrial, and other cancer cells [68][69][70][71]. Several epidemiological studies have shown a consistent relationship between prolactin levels and known risk factors for breast cancer such as parity and age at menarche [68].…”

Regulation of the Sphingosine Kinase/Sphingosine 1-Phosphate Pathway

“…Similar to E2, prolactin biphasically activates SK1 with acute activation of SK1 and late phase activation via SK1 gene transcription (Fig. 2) (Doll et al 2007). Lastly, progesterone has been shown to regulate SK1.…”