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

中文翻译：

---

神经酰胺在协调基于类视色素的癌症治疗中的作用

鞘脂介导的癌症发展和治疗调节主要以神经酰胺为中心，复杂的鞘脂代谢途径作为抗癌药物发现的有吸引力的靶点展开。鞘脂的动态相互转换在酶和细胞区室水平受到严格控制，以响应内源性或外源性刺激，例如抗癌药物，包括类视黄醇。在过去的二十年里，有证据表明类视色素在癌症治疗中的部分效力归功于调节鞘脂代谢和神经酰胺的产生。神经酰胺被认为是一种“肿瘤抑制脂质”，可以协调细胞生长、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，促肿瘤鞘脂的失调促进了癌症的发展，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。由于肿瘤抑制因子和肿瘤促进因子鞘脂的相反作用之间的平衡被破坏，可能会产生对癌症治疗的抗性。尽管鞘脂通路具有起伏的影响和复杂性，但存在大量酶靶向治疗干预措施的新兴机会，这些干预措施克服了鞘脂通路紊乱引起的耐药性。在这里，我们重新审视了鞘脂代谢的相互联系以及神经酰胺生物合成和降解酶的工具作用，包括生物活性鞘脂产品，它们如何与癌症治疗和发病机制密切相关，以及与癌症中类视色素信号的相互作用。我们专注于单独或组合针对癌症中的鞘脂代谢节点的类视黄醇靶向，以增强基于神经酰胺的疗法。使用新策略（例如联合治疗、合成类视黄醇、神经酰胺调节剂和递送制剂）的类视黄醇和基于神经酰胺的癌症治疗在抗癌斗争中大有希望