Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
Department of Pediatrics and Adolescent Medicine, Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon.
Biochem J. 2021 Oct 15;478(19):3621-3642. doi: 10.1042/BCJ20210368.
Sphingolipid-mediated regulation in cancer development and treatment is largely ceramide-centered with the complex sphingolipid metabolic pathways unfolding as attractive targets for anticancer drug discovery. The dynamic interconversion of sphingolipids is tightly controlled at the level of enzymes and cellular compartments in response to endogenous or exogenous stimuli, such as anticancer drugs, including retinoids. Over the past two decades, evidence emerged that retinoids owe part of their potency in cancer therapy to modulation of sphingolipid metabolism and ceramide generation. Ceramide has been proposed as a 'tumor-suppressor lipid' that orchestrates cell growth, cell cycle arrest, cell death, senescence, autophagy, and metastasis. There is accumulating evidence that cancer development is promoted by the dysregulation of tumor-promoting sphingolipids whereas cancer treatments can kill tumor cells by inducing the accumulation of endogenous ceramide levels. Resistance to cancer therapy may develop due to a disrupted equilibrium between the opposing roles of tumor-suppressor and tumor-promoter sphingolipids. Despite the undulating effect and complexity of sphingolipid pathways, there are emerging opportunities for a plethora of enzyme-targeted therapeutic interventions that overcome resistance resulting from perturbed sphingolipid pathways. Here, we have revisited the interconnectivity of sphingolipid metabolism and the instrumental role of ceramide-biosynthetic and degradative enzymes, including bioactive sphingolipid products, how they closely relate to cancer treatment and pathogenesis, and the interplay with retinoid signaling in cancer. We focused on retinoid targeting, alone or in combination, of sphingolipid metabolism nodes in cancer to enhance ceramide-based therapeutics. Retinoid and ceramide-based cancer therapy using novel strategies such as combination treatments, synthetic retinoids, ceramide modulators, and delivery formulations hold promise in the battle against cancer.
鞘脂代谢在癌症发生和治疗中的调控主要以神经酰胺为中心，复杂的鞘脂代谢途径的展开为抗癌药物发现提供了有吸引力的靶点。鞘脂的动态相互转化在酶和细胞区室水平受到内源性或外源性刺激（如抗癌药物，包括类视黄醇）的严格控制。在过去的二十年中，有证据表明，类视黄醇在癌症治疗中的部分效力归因于鞘脂代谢和神经酰胺生成的调节。神经酰胺已被提出为一种“肿瘤抑制脂质”，可协调细胞生长、细胞周期停滞、细胞死亡、衰老、自噬和转移。越来越多的证据表明，癌症的发生是由促进肿瘤的鞘脂失调所促进的，而癌症治疗可以通过诱导内源性神经酰胺水平的积累来杀死肿瘤细胞。由于肿瘤抑制和促进肿瘤的鞘脂的作用之间的平衡被打破，可能会对癌症治疗产生耐药性。尽管鞘脂途径的波动效应和复杂性，但仍然存在着大量酶靶向治疗干预的新机会，可以克服由于鞘脂途径失调而导致的耐药性。在这里，我们重新审视了鞘脂代谢的相互关联性，以及神经酰胺生物合成和降解酶的重要作用，包括生物活性鞘脂产物，它们如何与癌症治疗和发病机制密切相关，以及与癌症中的视黄醇信号转导的相互作用。我们专注于视黄醇对癌症中鞘脂代谢节点的靶向作用，单独或联合使用，以增强基于神经酰胺的治疗。使用新型策略的视黄醇和神经酰胺为基础的癌症治疗，如联合治疗、合成视黄醇、神经酰胺调节剂和递药制剂，在与癌症的斗争中具有很大的潜力。
