Aberrant energy metabolism represents a hallmark of cancer and contributes to numerous aggressive behaviors of cancer cells, including cell death and survival. Despite the poor prognosis of mantle cell lymphoma (MCL), due to the inevitable development of drug resistance, metabolic reprograming of MCL cells remains an unexplored area. Posttranslational modification of proteins via O-GlcNAcylation is an ideal sensor for nutritional changes mediated by O-GlcNAc transferase (OGT) and is removed by O-GlcNAcase (OGA). Using various small-molecule inhibitors of OGT and OGA, we found for the first time that O-GlcNAcylation potentiates MCL response to bortezomib. CRISPR interference of MGEA5 (encoding OGA) validated the apoptosis sensitization by O-GlcNAcylation and OGA inhibition. To identify the potential clinical candidates, we tested MCL response to drug-like OGA inhibitor, ketoconazole, and verified that it exerts similar sensitizing effect on bortezomib-induced apoptosis. Investigations into the underlying molecular mechanisms reveal that bortezomib and ketoconazole act in concert to cause the accumulation of truncated Bid (tBid). Not only does ketoconazole potentiate tBid induction, but also increases tBid stability through O-GlcNAcylation that interferes with tBid ubiquitination and proteasomal degradation. Remarkably, ketoconazole strongly enhances bortezomib-induced apoptosis in de novo bortezomib-resistant MCL cells and in patient-derived primary cells with minimal cytotoxic effect on normal peripheral blood mononuclear cells and hepatocytes, suggesting its potential utility as a safe and effective adjuvant for MCL. Together, our findings provide novel evidence that combination of bortezomib and ketoconazole or other OGA inhibitors may present a promising strategy for the treatment of drug-resistant MCL. Mol Cancer Ther; 17(2); 484–96. ©2017 AACR.

中文翻译：

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抑制 O-GlcNAcase 通过修饰截短的 Bid 使细胞凋亡敏感并逆转套细胞淋巴瘤中的硼替佐米耐药

异常的能量代谢代表了癌症的标志，并导致了癌细胞的多种攻击行为，包括细胞死亡和存活。尽管套细胞淋巴瘤 (MCL) 的预后较差，但由于耐药性的不可避免的发展，MCL 细胞的代谢重编程仍然是一个未开发的领域。通过 O-GlcNAcylation 对蛋白质进行翻译后修饰是由 O-GlcNAc 转移酶 (OGT) 介导的营养变化的理想传感器，并被 O-GlcNAcase (OGA) 去除。使用 OGT 和 OGA 的各种小分子抑制剂，我们首次发现 O-GlcNAcylation 可增强 MCL 对硼替佐米的反应。MGEA5（编码 OGA）的 CRISPR 干扰验证了 O-GlcNAcylation 和 OGA 抑制对细胞凋亡的敏感性。为了确定潜在的临床候选人，我们测试了 MCL 对药物样 OGA 抑制剂酮康唑的反应，并证实它对硼替佐米诱导的细胞凋亡具有类似的敏化作用。对潜在分子机制的研究表明，硼替佐米和酮康唑协同作用导致截断 Bid (tBid) 的积累。酮康唑不仅可以增强 tBid 的诱导作用，还可以通过干扰 tBid 泛素化和蛋白酶体降解的 O-GlcNAcylation 增加 tBid 稳定性。值得注意的是，酮康唑在新的硼替佐米耐药 MCL 细胞和患者来源的原代细胞中强烈增强硼替佐米诱导的细胞凋亡，对正常外周血单核细胞和肝细胞的细胞毒性作用最小，表明其作为 MCL 安全有效佐剂的潜在用途。一起，我们的研究结果提供了新的证据，表明硼替佐米和酮康唑或其他 OGA 抑制剂的组合可能是治疗耐药 MCL 的有希望的策略。摩尔癌症治疗; 17(2); 484-96。©2017 AACR。