Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Mol Cancer Ther. 2018 Feb;17(2):484-496. doi: 10.1158/1535-7163.MCT-17-0390. Epub 2017 Nov 22.
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 GlcNAcylation is an ideal sensor for nutritional changes mediated by -GlcNAc transferase (OGT) and is removed by -GlcNAcase (OGA). Using various small-molecule inhibitors of OGT and OGA, we found for the first time that GlcNAcylation potentiates MCL response to bortezomib. CRISPR interference of (encoding OGA) validated the apoptosis sensitization by 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 GlcNAcylation that interferes with tBid ubiquitination and proteasomal degradation. Remarkably, ketoconazole strongly enhances bortezomib-induced apoptosis in 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. .
异常的能量代谢是癌症的一个标志，有助于癌细胞的许多侵袭性行为，包括细胞死亡和存活。尽管套细胞淋巴瘤（MCL）的预后较差，但由于不可避免地会产生耐药性，MCL 细胞的代谢重编程仍然是一个未被探索的领域。通过 GlcNAcylation 对蛋白质进行翻译后修饰是一种理想的传感器，可以感应由β-GlcNAc 转移酶（OGT）介导的营养变化，并且可以被β-GlcNAcase（OGA）去除。使用 OGT 和 OGA 的各种小分子抑制剂，我们首次发现 GlcNAcylation 增强了 MCL 对硼替佐米的反应。通过 CRISPR 干扰（编码 OGA），验证了 GlcNAcylation 和 OGA 抑制对细胞凋亡的敏化作用。为了确定潜在的临床候选药物，我们测试了 MCL 对类似药物的 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相似的敏化作用。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。酮康唑不仅增强了 tBid 的诱导作用，而且通过干扰 tBid 的泛素化和蛋白酶体降解来增加 tBid 的稳定性。值得注意的是，酮康唑强烈增强了对硼替佐米耐药的 MCL 细胞和源自患者的原代细胞中硼替佐米诱导的细胞凋亡，而对正常外周血单核细胞和肝细胞的细胞毒性很小，这表明它作为一种安全有效的 MCL 辅助药物具有潜在的用途。总之，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 抑制剂的联合使用可能为治疗耐药性 MCL 提供一种有前途的策略。
