Sphingosine 1-phosphate (S1P), produced by two sphingosine kinase isoenzymes, denoted SphK1 and SphK2, is the ligand for a family of five specific G protein-coupled receptors that regulate cytoskeletal rearrangements and cell motility. Whereas many growth factors stimulate SphK1, much less is known of the regulation of SphK2. Here we report that epidermal growth factor (EGF) stimulated SphK2 in HEK 293 cells. This is the first example of an agonist-dependent regulation of SphK2. Chemotaxis of HEK 293 cells toward EGF was inhibited by N,N-dimethylsphingosine, a competitive inhibitor of both SphKs, implicating S1P generation in this process. Down-regulating expression of SphK1 in HEK 293 cells with a specific siRNA abrogated migration toward EGF, whereas decreasing SphK2 expression had no effect. EGF contributes to the invasiveness of human breast cancer cells, and EGF receptor expression is associated with poor prognosis. EGF also stimulated SphK2 in MDA-MB-453 breast cancer cells. Surprisingly, however, down-regulation of SphK2 in these cells completely eliminated migration toward EGF without affecting fibronectin-induced haptotaxis. Our results suggest that SphK2 plays an important role in migration of MDA-MB-453 cells toward EGF.
This article describes a novel role of Cdc25A down-regulation during differentiation of proliferating myoblasts.
Sphingosine-1-phosphate (S1P) is a potent lysolipid involved in a variety of biological responses important for cancer progression. Therefore, we investigated the role of sphingosine kinase type 1 (SphK1), the enzyme that makes S1P, in the motility, growth, and chemoresistance of MCF-7 breast cancer cells. Epidermal growth factor (EGF), an important growth factor for breast cancer progression, activated and translocated SphK1 to plasma membrane. SphK1 was required for EGF-directed motility. Downregulation of SphK1 in MCF-7 cells reduced EGF-and serum-stimulated growth and enhanced sensitivity to doxorubicin, a potent chemotherapeutic agent. These results suggest that SphK1 may be critical for growth, metastasis and chemoresistance of human breast cancers.
Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, is the ligand for five specific G proteincoupled receptors, named S1P 1 to S1P 5 . In this study, we found that cross-communication between plateletderived growth factor receptor and S1P 2 serves as a negative damper of PDGF functions. Deletion of the S1P 2 receptor dramatically increased migration of mouse embryonic fibroblasts toward S1P, serum, and PDGF but not fibronectin. This enhanced migration was dependent on expression of S1P 1 and sphingosine kinase 1 (SphK1), the enzyme that produces S1P, as revealed by downregulation of their expression with antisense RNA and small interfering RNA, respectively. Although S1P 2 deletion had no significant effect on tyrosine phosphorylation of the PDGF receptors or activation of extracellular signal-regulated kinase 1/2 or Akt induced by PDGF, it reduced sustained PDGF-dependent p38 phosphorylation and markedly enhanced Rac activation. Surprisingly, S1P 2 -null cells not only exhibited enhanced proliferation but also markedly increased SphK1 expression and activity. Conversely, reintroduction of S1P 2 reduced DNA synthesis and expression of SphK1. Thus, S1P 2 serves as a negative regulator of PDGF-induced migration and proliferation as well as SphK1 expression. Our results suggest that a complex interplay between PDGFR and S1P receptors determines their functions.Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite formed by activation of SphK by many stimuli, including platelet-derived growth factor (PDGF) (43, 48). As a specific ligand for a family of five G protein-coupled receptors (GPCRs), S1P 1 to S1P 5 (2, 48), S1P regulates a wide variety of important cellular processes, including cytoskeletal rearrangements and cell movement (17,25,45,49,57), angiogenesis and vascular maturation (14,16,26,32,57), and immunity and lymphocyte trafficking (33,34). Interestingly, all of the S1P receptors (S1PRs) have been shown to play critical roles in cytoskeletal reorganization and cell migration (13,26,57). Activation of S1P 1 or S1P 3 increases directional or chemotactic migration (14, 27, 57), and both mediate activation of Rac via G i (26,38). In contrast, ligation of S1P 2 decreases chemotaxis and membrane ruffling (49), due to suppression of Rac activation, probably by stimulation of a GTPase-activating protein for Rac (38). Interestingly, the repellant receptor S1P 2 and the attractant receptor S1P 3 similarly stimulate RhoA activity, likely via G 12/13 (21). Recent studies suggest that the balance of counteracting signals from the G i -and the G 12/13 -Rho pathways directs either positive or negative regulation of Rac and cell migration (49). Similar to its functions in lower organisms, including yeasts and plants, which do not have S1PRs, S1P may also have intracellular actions important for calcium homeostasis (36), cell growth (40, 56), and stress responses (9,11,37,42). S1P, like various other GPCR agonists, can activate growth factor tyrosine kinase receptors in the absence of added...
The androgen receptor (AR) has a vital role in the onset and progression of prostate cancer by promoting G1-S progression, possibly by functioning as a licensing factor for DNA replication. We here report that low dose 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite, induces mitotic arrest in prostate cancer cells involving activation of the E3 ligase CHIP (Cterminus of Hsp70-interacting protein) and degradation of the AR. Depletion of the AR by small interfering RNA (siRNA) eliminates 2-ME-induced arrest and introducing AR into PC3-M cells confers 2-ME-induced mitotic arrest. Knockdown of CHIP or MDM2 (mouse homolog of double minute 2 protein) individually or in combination reduced AR degradation and abrogated M phase arrest induced by 2-ME. Our data link AR degradation via ubiquitination to mitotic arrest. Targeting the AR by activating E3 ligases such as CHIP represents a novel strategy for the treatment of prostate cancer.
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