Key Points The synthetic retinoid ST1926 induces apoptosis of ATL cells and prolongs survival of ATL mice. At the molecular level, ST1926 causes early DNA damage, upregulates p53, and downregulates Tax expression.

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

Ceramide (Cer) is a bioactive cellular lipid with compartmentalized and tightly regulated levels. Distinct metabolic pathways lead to the generation of Cer species with distinguishable roles in oncogenesis. Deregulation of Cer pathways has emerged as an important mechanism for acquired chemotherapeutic resistance. Adult T-cell leukemia (ATL) cells are defective in Cer synthesis. ATL is an aggressive neoplasm that develops following infection with human T cell lymphotropic virus-1 (HTLV-1) where the viral oncogene Tax contributes to the pathogenesis of the disease. ATL cells, resistant to all-trans-retinoic acid, are sensitive to pharmacologically achievable concentrations of the synthetic retinoid ST1926. We studied the effects of ST1926 on Cer pathways in ATL cells. ST1926 treatment resulted in early Tax oncoprotein degradation in HTLV-1 treated cells. ST1926 induced cell death and a dose- and time-dependent accumulation of Cer in malignant T cells. The kinetics and degree of Cer production showed an early response upon ST1926 treatment. ST1926 enhanced de novo Cer synthesis via activation of ceramide synthase CerS(s) without inhibiting dihydroceramide desaturase, thereby accumulating Cer rather than the less bioactive dihydroceramide. Using labeling experiments with the unnatural 17-carbon sphinganine and measuring the generated Cer species, we showed that ST1926 preferentially induces the activities of a distinct set of CerS(s). We detected a delay in cell death response and interruption of Cer generation in response to ST1926 in Molt-4 cells overexpressing Bcl-2. These results highlight the potential role of ST1926 in inducing Cer levels, thus lowering the threshold for cell death in ATL cells.