Hii Ling-Wei, Chung Felicia Fei-Lei, Mai Chun-Wai, Ng Pei Yuen, Leong Chee-Onn
Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia.
Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia.
Front Mol Biosci. 2021 Nov 8;8:748470. doi: 10.3389/fmolb.2021.748470. eCollection 2021.
Sphingosine kinases (SPHKs) are conserved lipid enzymes that catalyze the formation of sphingosine-1-phosphate (S1P) through ATP-dependent phosphorylation of sphingosine. Two distinct SPHK isoforms, namely SPHK1 and SPHK2, have been identified to date, and the former has been implicated for its oncogenic roles in cancer development and progression. While SPHK1 signaling axis has been extensively studied in non-stem breast cancer cells, recent evidence has emerged to suggest a role of SPHK1 in regulating cancer stem cells (CSCs). With the clinical implications of CSCs in disease relapse and metastasis, it is believed that therapeutic approaches that can eradicate both non-stem cancer cells and CSCs could be a key to cancer cure. In this review, we first explore the oncogenic functions of sphingosine kinase 1 in human cancers and summarize current research findings of SPHK1 signaling with a focus on breast cancer. We also discuss the therapeutic potentials and perspectives of targeting SPHK1 signaling in breast cancer and cancer stem cells. We aim to offer new insights and inspire future studies looking further into the regulatory functions of SPHK1 in CSC-driven tumorigenesis, uncovering novel therapeutic avenues of using SPHK1-targeted therapy in the treatment of CSC-enriched refractory cancers.
鞘氨醇激酶（SPHKs）是一类保守的脂类酶，可通过对鞘氨醇进行ATP依赖性磷酸化来催化生成1-磷酸鞘氨醇（S1P）。迄今已鉴定出两种不同的SPHK亚型，即SPHK1和SPHK2，前者因在癌症发生发展过程中具有致癌作用而受到关注。虽然SPHK1信号轴已在非干细胞性乳腺癌细胞中得到广泛研究，但最近有证据表明SPHK1在调节癌症干细胞（CSCs）方面发挥作用。鉴于CSCs在疾病复发和转移中的临床意义，人们认为能够根除非干细胞性癌细胞和CSCs的治疗方法可能是治愈癌症的关键。在这篇综述中，我们首先探讨鞘氨醇激酶1在人类癌症中的致癌功能，并总结SPHK1信号传导的当前研究结果，重点关注乳腺癌。我们还讨论了针对乳腺癌和癌症干细胞中SPHK1信号传导的治疗潜力和前景。我们旨在提供新的见解，并激发未来的研究，进一步深入研究SPHK1在CSC驱动的肿瘤发生中的调节功能，揭示使用SPHK1靶向治疗来治疗富含CSC的难治性癌症的新治疗途径。
