Sphingosine kinase 1 overexpression is regulated by signaling through PI3K, AKT2, and mTOR in imatinib-resistant chronic myeloid leukemia cells

Abstract

Objective. As a better understanding of the molecular basis of carcinogenesis has emerged, oncogene-specific cell-signaling pathways have been successfully targeted to treat human malignances. Despite impressive advances in oncogene-directed therapeutics, genetic instability in cancer cells often manifest acquired resistance. This is particularly noted in the use of tyrosine kinase inhibitors therapies and not more evident than for chronic myeloid leukemia. Therefore, it is of great importance to understand the molecular mechanisms affecting cancer cell sensitivity and resistance to tyrosine kinase inhibitors. Materials and Methods. In this study, we used continuous exposure to stepwise increasing concentrations of imatinib (0.6L1 mM) to select imatinib-resistant K562 cells. Results. Expression of BCR-ABL increased both at RNA and protein levels in imatinib-resistant cell lines. Furthermore, expression levels of sphingosine kinase 1 (SphK1) were increased significantly in resistant cells, channeling sphingoid bases to the SphK1 pathway and activating sphingosine-1-phosphateLdependent tyrosine phosphorylation pathways that include the adaptor protein Crk. The partial inhibition of SphK1 activity by N,N-dimethylsphingosine or expression by small interfering RNA increased sensitivity to imatinib-induced apoptosis in resistant cells and returned BCR-ABL to baseline levels. To determine the resistance mechanism-induced SphK1 upregulation, we used pharmacological inhibitors of the phosphoinositide 3-kinase/ AKT/mammalian target of rapamycin signaling pathway and observed robust downmodulation of SphK1 expression and activity when AKT2, but not AKT1 or AKT3, was suppressed.Conclusions. These results demonstrate that SphK1 is upregulated in imatinib-resistant K562 cells by a pathway contingent on a phosphoinositide 3-kinase/AKT2/mammalian target of rapamycin signaling pathway. We propose that SphK1 plays an important role in development of acquired resistance to imatinib in chronic myeloid leukemia cell lines. Ó

Sphingosine Kinase 1 Overexpression Contributes to Cetuximab Resistance in Human Colorectal Cancer Models

“…Consistently, interference with SphK1 activity by dominant-negative mutants or competitive inhibitors such as N,N-dimethylsphingosine (DMS), as well as inhibition of S1P by mAbs or S1P receptors antagonists such as fingolimod (FTY720, Novartis), blocks tumorigenesis and tumor angiogenesis in cancer models (8). Moreover, recent studies showed that alterations of ceramide/S1P rheostat may be involved in the regulation of resistance to both chemotherapeutics and targeted agents (9)(10)(11)(12)(13)(14).…”

“…On the basis of the evidence that alterations of ceramide/ S1P rheostat may be involved in resistance to biologic agents (9,13,14) and as some reports showed cross-talks between SphK1 and EGFR-dependent pathways (15,16,31), we investigated the role of SphK1 in the onset of resistance to cetuximab in colorectal cancers. To this aim, we analyzed SphK1 expression and activation in preclinical models of colorectal cancer, both sensitive or with intrinsic/ acquired resistance to cetuximab.…”

“…On the basis of this body of data, and as alterations of ceramide/S1P rheostat mediated by SphK1 overexpression have been involved in reduced response to therapy in human cancers (9)(10)(11)(12)14), we evaluated SphK1 expression in paraffin-embedded, archived clinical tumor tissue specimens obtained from 50 cases of K-Ras wild-type colorectal cancer patients enrolled in controlled clinical trials and treated with cetuximab-containing regimens. To evaluate SphK1 expression, 3 different Abs were tested, but only one yielded a strong signal intensity (Supplementary Fig.…”

Sphingosine kinase 1 overexpression is associated with poor prognosis and oxaliplatin resistance in hepatocellular carcinoma

“…For example, raised SphK1 has been associated with chronic myeloid leukemia resistance to imatinib and pancreatic cancer cell resistance to gemcitabine (16,25). Conversely, SphK1 inhibition can sensitize CML and pancreatic cancer cells to the proapoptotic effects of gemcitabine and imatinib, respectively, apparently by increasing the ceramide/S1P ratio and thereby enabling C18-ceramide-dependent apoptosis to proceed (16,25). Moreover, blockade of the SphK1 signaling pathway may reprogram cellular responsiveness to tamoxifen and abrogate antiestrogen resistance in human breast cancer cells (14).…”

Export of sphingosine-1-phosphate and cancer progression

“…In addition to cancer cells, tumors contain a repertoire of recruited ostensibly normal cells that contribute to cancer biology by creating the tumor microenvironment. Cancer cells do not manifest the disease alone, but rather conscript and corrupt resident and recruited normal cells, and collaborative ( 31 ), colon ( 34,35 ), breast ( 36,37 ), prostate ( 38 ), nonHodgkin's lymphoma ( 39 ), chronic myeloid leukemia ( 40 ), astrocytoma ( 41 ), and glioblastoma ( 42 ). In several of these studies, increased SphK1 expression correlated with increased tumor grade and poor prognosis.…”