Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells

Abstract

We examined the involvement of sphingosine kinase-1 (SphK1), which governs the ceramide/sphingosine-1-phosphate balance, in susceptibility to imatinib of either sensitive or resistant chronic myeloid leukemia cells. Imatinib-sensitive LAMA84-s displayed marked SphK1 inhibition coupled with increased content of ceramide and decreased pro-survival sphingosine-1-phosphate. Conversely, no changes in the sphingolipid metabolism were observed in LAMA84-r treated with imatinib. Overcoming imatinib resistance in LAMA84-r with farnesyltransferase or MEK/ERK inhibitors as well as with cytosine arabinoside led to SphK1 inhibition. Overexpression of SphK1 in LAMA84-s cells impaired apoptosis and inhibited the effects of imatinib on caspase-3 activation, cytochrome c and Smac release from mitochondria through modulation of Bim, Bcl-xL and Mcl-1 expression. Pharmacological inhibition of SphK1 with F-12509a or its silencing by siRNA induced apoptosis of both imatinib-sensitive and -resistant cells, suggesting that SphK1 inhibition was critical for apoptosis signaling. We also show that imatinib-sensitive and -resistant primary cells from chronic myeloid leukemia patients can be successfully killed in vitro by the F-12509a inhibitor. These results uncover the involvement of SphK1 in regulating imatinib-induced apoptosis and establish that SphK1 is a downstream effector of the BcrAbl/Ras/ERK pathway inhibited by imatinib but upstream regulator of Bcl-2 family members.

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

“…It was also shown that intracellular concentrations of ceramides are increased in response to stress conditions. But in cancerous tissues and cells and in more agressive resistant cell expressions, levels of GCS and SK-1 increases significantly [26][27][28].…”

“…Ceramides act as strong antitumoral molecules supressing cell growth and proliferation and inducing apoptosis and differentiation [26]. On the other hand, GlcCer and S1P molecules converted from ceramide by glucosylceramide synthase (GCS) and sphingosine kinase-1 (SK-1) enzymes act as strong antiapoptotic molecules inducing cell growth and proliferation and inhibiting apoptosis and differentiation [27,28]. Thus, the balance between ceramide/GlcCer or ceramide/S1P significantly affects the fate of the cell to die or to survive.…”

Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug

“…Consistently, antibodies targeting S1P have been recently shown to have a significant antineoplastic potential (11), and clinical trials using inhibitors of SphK1 in combination with chemotherapeutic treatments are ongoing for chemotherapy-resistant ovarian cancers and hormonerefractory prostate cancers. Recently, we and other groups have correlated resistance to anticancer therapies of several cancer cell lines with a defect in both ceramide production and/or SphK1 inhibition (9,12,13). In these conditions, the concept that SphK1 inhibition might sensitize resistant cancer cells to these inefficient therapies has emerged.…”

Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells

“…Imatinib was the first tyrosine kinase inhibitor used to specifically recognize the adenosine triphosphate (ATP) binding site of the BCR-ABL protein. However, its continuous administration was associated with the development of resistance, especially in the advanced phase or blast crisis [8]. Different mechanisms were suggested for imatinib resistance [9,10] such as mutations in the ATP binding site of BCR-ABL [11], decreased availability of the drug either by binding to plasma proteins or by overexpression of transporter proteins such as P-glycoprotein on the plasma membrane [12], or overexpression of BCR-ABL.…”