A Novel Mode of Action of the Putative Sphingosine Kinase Inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) Thiazole (SKI II): Induction of Lysosomal Sphingosine Kinase 1 Degradation

Ren, Shen; Xin, Cuiyan; Pfeilschifter, Josef; Huwiler, Andrea

doi:10.1159/000315110

Cited by 58 publications

(56 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, SKI-II mediates the proteasome-dependent degradation of SK-1, leading to the inhibition of S1P generation. 43 Consistent with these data, our results indicate that pharmacologic and/or molecular inhibition of SK-1 help overcome drug resistance in CML cells via inducing PP2A-dependent dephosphorylation/inactivation and degradation of Bcr-Abl1.In this study, we also showed that S1P2 signaling contributes to drug resistance in CML via attenuation of Bcr-Abl1 dephosphorylation/degradation. Overexpression of S1P2 was not sufficient to induce drug resistance, and it required the addition of S1P in K562 cells, suggesting that SK-1-generated S1P is necessary for the inhibition of PP2A and regulation of imatinib resistance upstream of S1P2 signaling.…”

supporting

confidence: 89%

Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A

Salas

Ponnusamy

Senkal

et al. 2011

Blood

104

106

View full text Add to dashboard Cite

Introduction CML is a clonal disorder of pluripotent hematopoietic stem cells characterized by the Philadelphia (Ph) chromosome, which results from the reciprocal translocation between the long arms of chromosomes 9 and 22. 1-4 This hybrid B-cell receptor (BCR)-ABL1 gene encodes for a fusion protein Bcr-Abl1 with a constitutive tyrosine kinase activity. 3,4 Despite high rates of clinical responses in early chronic phase CML (CML-CP) to the Bcr-Abl1 kinase inhibitor imatinib, 5-8 development of resistance is a major problem in late CML-CP and in the treatment of blast crisis CML (CML-BC). 9-12 Although Bcr-Abl1-independent mechanisms also exist, 13-15 resistance in CML-CP is usually associated with the expression of mutant Bcr-Abl1 proteins, including T315I and Y253F/H mutations against which the second generation ABL tyrosine kinase inhibitors (TKI) such as nilotinib and/or dasatinib show limited effect. 15-17 Nonetheless , BCR-ABL1 mutations may not account for all cases of drug resistance in CML (CP and BC); indeed, alternative Bcr-Abl1-dependent mechanisms including alterations of sphingolipid metabolism and signaling, 18 might account for TKI resistance. Sphingolipids, ceramide and sphingosine 1-phosphate (S1P) included, are a family of membrane lipids with important roles in the regulation of the fluidity and subdomain structure of membranes. 19-21 Ceramide can be hydrolyzed by ceramidases to release sphingosine, which is phosphorylated by sphingosine kinases-1 or-2 (SK-1 or SK-2) to generate S1P. 20 Ceramide plays proapoptotic roles 21 whereas S1P mediates proliferation and/or resistance to apoptosis 22,23 generally via G-protein-coupled S1P1-5 receptor signaling. 24 However, receptor-independent intracellular functions of S1P were also reported. 25 Recently, alteration of the balance between the proapoptotic ceramide and antiapoptotic S1P via up-regulation of SK-1 was shown to mediate imatinib resistance in K562 CML-BC patient-derived cells by an unknown mechanism. 18 Here, we report the identification of a novel mechanism by which SK-1/S1P mediates imatinib resistance by regulation of the PP2A-dependent and SHP-1-mediated Bcr-Abl1 dephosphoryla-tion and stability selectively via receptor 2 (S1P2) signaling in CML (CP and BC). In addition, our data suggest that targeting the SK-1/S1P2 signaling axis provides a novel strategy to modulate wild-type (wt) or mutant (T315I or Y253H) Bcr-Abl1 stability by restoring PP2A function, and attenuate drug resistance both in cell culture and in mice bearing 32D/T315I-Bcr-Abl1 allografts. Human CML cell lines K562, LAMA4, and their imatinib-resistant derivatives K562/IMA-0.1,-1,-3, or LAMA4/IMA, were maintained as described. 18 The Bcr-Abl-expressing 32Dcl3 cells, 32D-p210 Bcr-Abl (wt), 32D-p210 Bcr-Abl (Y253H) and (T315I) were maintained in RPMI containing 15% FBS, 2mM L-glutamine, and penicillin and streptomycin (P/S; 100 ng/mL each). MEFs (wt and SK-1 /) were maintained in DMEM with 10% FBS and P/S. Human CD34 primary cells from CML patients and normal donor were obt...

show abstract

supporting

confidence: 89%

Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A

Salas

Ponnusamy

Senkal

et al. 2011

Blood

104

106

View full text Add to dashboard Cite

show abstract

“…The biologic significance of different SphK1 forms is not known, although it has been suggested that they exhibit different subcellular localization (40) and may therefore have functional specificity. The SphK1 variants were all decreased by SKi-II and, as in other cell types (27,41,42), this was reversed by the proteasome inhibitor MG132, implying their degradation via ubiquitin-proteasomal pathways. MG132 also increased various SphK1 forms to levels above those in untreated cells, suggesting proteasome regulation of the enzyme under basal conditions.…”

Section: Discussionmentioning

confidence: 72%

Inhibition of Insulin-like Growth Factor–Binding Protein-3 Signaling through Sphingosine Kinase-1 Sensitizes Triple-Negative Breast Cancer Cells to EGF Receptor Blockade

Martin

Silva

Lin

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The type I EGF receptor (EGFR or ErbB1) and insulin-like growth factor-binding protein-3 (IGFBP-3) are highly expressed in triple-negative breast cancer (TNBC), a particularly aggressive disease that cannot be treated with conventional therapies targeting the estrogen or progesterone receptors (ER and PR), or HER2. We have shown previously in normal breast epithelial cells that IGFBP-3 potentiates growth-stimulatory signaling transduced by EGFR, and this is mediated by the sphingosine kinase-1 (SphK1)/sphingosine 1-phosphate (S1P) system. In this study, we investigated whether cotargeting the EGFR and SphK1/S1P pathways in TNBC cells results in greater growth inhibition compared with blocking either alone, and might therefore have novel therapeutic potential in TNBC. In four TNBC cell lines, exogenous IGFBP-3 enhanced ligand-stimulated EGFR activation, associated with increased SphK1 localization to the plasma membrane. The effect of exogenous IGFBP-3 on EGFR activation was blocked by pharmacologic inhibition or siRNA-mediated silencing of SphK1, and silencing of endogenous IGFBP-3 also suppressed EGF-stimulated EGFR activation. Real-time analysis of cell proliferation revealed a combined effect of EGFR inhibition by gefitinib and SphK1 inhibition using SKi-II. Growth of MDA-MB-468 xenograft tumors in mice was significantly inhibited by SKi-II and gefitinib when used in combination, but not as single agents. We conclude that IGFBP-3 promotes growth of TNBC cells by increasing EGFR signaling, that this is mediated by SphK1, and that combined inhibition of EGFR and SphK1 has potential as an anticancer therapy in TNBC in which EGFR and IGFBP-3 expression is high. Mol Cancer Ther; 13(2); 316-28. Ó2013 AACR.

show abstract

“…S2). In addition to this, others have reported, using the cathepsin B inhibitor, CA074Me, that SKi induces lysosomal degradation of SK1 in human podocytes (32). To investigate the role for lysosomal degradation of SK1a/b in response to SKi, we pretreated LNCaP cells with CA074Me.…”

Section: Effect Of Sk1 Inhibitors In Human Pulmonary Artery Smooth Mumentioning

confidence: 94%

The Sphingosine Kinase 1 Inhibitor 2-(p-Hydroxyanilino)-4-(p-chlorophenyl)thiazole Induces Proteasomal Degradation of Sphingosine Kinase 1 in Mammalian Cells

Loveridge

Tonelli

Leclercq

et al. 2010

Journal of Biological Chemistry

110

209

View full text Add to dashboard Cite

Sphingosine kinase 1 (SK1) is an enzyme that catalyzes the phosphorylation of sphingosine to produce the bioactive lipid sphingosine 1-phosphate (S1P). We demonstrate here that the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) induces the proteasomal degradation of SK1 in human pulmonary artery smooth muscle cells, androgen-sensitive LNCaP prostate cancer cells, MCF-7 and MCF-7 HER2 breast cancer cells and that this is likely mediated by ceramide as a consequence of catalytic inhibition of SK1 by SKi. Moreover, SK1 is polyubiquitinated under basal conditions, and SKi appears to increase the degradation of SK1 by activating the proteasome. In addition, the proteasomal degradation of SK1a and SK1b in androgen-sensitive LNCaP cells is associated with the induction of apoptosis. However, SK1b in LNCaP-AI cells (androgen-independent) is less sensitive to SKi-induced proteasomal degradation and these cells are resistant to SKi-induced apoptosis, thereby implicating the ubiquitin-proteasomal degradation of SK1 as an important mechanism controlling cell survival.Sphingosine 1-phosphate (S1P) 5 is a bioactive lipid that has an important role in regulating the growth, survival, and migration of mammalian cells. S1P binds to a family of five GPCR termed S1P n (where n ϭ 1-5) that regulate various effectors, such as MAP kinase (1). S1P is produced by the enzyme sphingosine kinase (SK1 and SK2 isoforms), which catalyzes the phosphorylation of sphingosine to produce S1P (2, 3). There are three N-terminal variants of SK1. SK1a (GenBank TM number: NM_001142601) is a 42.5 kDa protein, while SK1b (GenBank TM number: NM_182965) is a 51 kDa protein identical to SK1a, but with an 86 amino acid N-terminal extension. The third form has a molecular mass of 43.9 kDa and is identical to SK1a except for a 14 amino acid Nterminal extension (GenBank TM number: NM_021972) and migrates with similar mobility as SK1a on SDS-PAGE. The SK1a annotation used here therefore includes SK1a and possibly SK1aϩ14.SK1 has been demonstrated to have an important role in cancer (4). For instance, enforced overexpression of SK1 increases V12-Ras-dependent transformation of cancer cells (5), S1P levels, estrogen-dependent tumorigenesis, and blocks apoptosis of MCF-7 cells induced by anti-cancer drugs (6). SK1/S1P is also required for EGF-induced MCF-7 cell migration, proliferation and survival (7) and breast cancer cell growth (8). High SK1 expression is also correlated with poor prognosis in ER ϩ breast cancer, and SK1 induces a migratory phenotype in response to S1P in MCF-7 cells, via SK1-dependent changes in S1P 3 expression and PAK1/ERK-1/2 regulation (9). There is no evidence that mutations occur in the SK1 gene linked to cancer and therefore, the term non-oncogene addiction has been used to describe its role in cancer progression (10). The S1P signaling pathway has also been implicated in promoting the proliferation of androgen-independent prostate cancer PC-3 cells (11). Moreover, irradiation of a radiation-sensitive cancer cell ...

show abstract

A Novel Mode of Action of the Putative Sphingosine Kinase Inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) Thiazole (SKI II): Induction of Lysosomal Sphingosine Kinase 1 Degradation

Cited by 58 publications

References 36 publications

Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A

Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A

Inhibition of Insulin-like Growth Factor–Binding Protein-3 Signaling through Sphingosine Kinase-1 Sensitizes Triple-Negative Breast Cancer Cells to EGF Receptor Blockade

The Sphingosine Kinase 1 Inhibitor 2-(p-Hydroxyanilino)-4-(p-chlorophenyl)thiazole Induces Proteasomal Degradation of Sphingosine Kinase 1 in Mammalian Cells

Contact Info

Product

Resources

About