Defining a role for sphingosine kinase 1 in p53-dependent tumors

Abstract

p53 is a crucial tumor suppressor that is mutated or deleted in a majority of cancers. Exactly how p53 prevents tumor progression has proved elusive for many years; however, this information is crucial to define targets for chemotherapeutic development that can effectively restore p53 function. Bioactive sphingolipids have recently emerged as important regulators of proliferative, apoptotic and senescent cellular processes. In this study, we demonstrate that the enzyme sphingosine kinase 1 (SK1), a critical enzyme in the regulation of the key bioactive sphingolipids ceramide, sphingosine and sphingosine-1-phosphate (S1P), serves as a key downstream target for p53 action. Our results show that SK1 is proteolysed in response to genotoxic stress in a p53-dependent manner. p53 null mice display elevation of SK1 levels and a tumor-promoting dysregulation of bioactive sphingolipids in which the anti-growth sphingolipid ceramide is decreased and the pro-growth sphingolipid S1P is increased. Importantly, deletion of SK1 in p53 null mice completely abrogated thymic lymphomas in these mice and prolonged their life span by ~30%. Deletion of SK1 also significantly attenuated the formation of other cancers in p53 heterozygote mice. The mechanism of p53 tumor suppression by loss of SK1 is mediated by elevations of sphingosine and ceramide, which in turn were accompanied by increased expression of cell cycle inhibitors and tumor cell senescence. Thus, targeting SK1 may restore sphingolipid homeostasis in p53-dependent tumors and provide insights into novel therapeutic approaches to cancer.

Recent advances in the development of sphingosine kinase inhibitors

“…The potential of SK2 as an oncology target has emerged more recently, with several SK2-selective inhibitors showing anti-cancer effects, with one progressing to clinical trials (see Section 4.1), and siRNA knockdown studies also showing the efficacy of targeting this isoform in some cancers, including acute lymphocytic leukaemia [36], multiple myeloma [37], glioblastoma [38] and kidney and breast cancer [39]. Notably, SK1 −/− or SK2 −/− mice have also shown reduced tumour growth in a number of in vivo cancer models [25][26][27][28][29][30][31][32]36,40]. These studies have rendered both SKs as attractive targets for drug development [34,35].…”

“…In addition to a large number of studies demonstrating the anti-cancer effects of SK1 inhibitors [25][26][27][28][29][30][31][32] (reviewed in [33,34]), siRNA knockdown of SK1 has also been shown to induce cell death and confer sensitivity to chemo-or radiation therapy of cancer lines (reviewed in [33][34][35]). The potential of SK2 as an oncology target has emerged more recently, with several SK2-selective inhibitors showing anti-cancer effects, with one progressing to clinical trials (see Section 4.1), and siRNA knockdown studies also showing the efficacy of targeting this isoform in some cancers, including acute lymphocytic leukaemia [36], multiple myeloma [37], glioblastoma [38] and kidney and breast cancer [39].…”

Molecular mechanisms of oncogene-induced inflammation and inflammation-sustained oncogene activation in gastrointestinal tumors: An underappreciated symbiotic relationship

“…Upregulation of NF-κB in these hematopoietic cells results in upregulation of IL6 and STAT3, which forms a feedback loop and upregulates S1PR1, thereby forming a malicious feedback loop between S1P and NF-κB /IL6/STAT3 in driving colitis and CRC (13, 16). Additionally, Sphk1 proteolysis is a direct target of p53 (17). Sphk1 deletion in p53 null mice prevented lymphoma incidence and increased median survival.…”

Sphingosine Kinase 1 Regulates Tumor Necrosis Factor-mediated RANTES Induction through p38 Mitogen-activated Protein Kinase but Independently of Nuclear Factor κB Activation

“…Ϫ/Ϫ fibroblasts were obtained as previously described (35). MEFs were generated from SK1Ϯ littermate matings in a C57BL6.129S background.…”