联合靶向套细胞淋巴瘤中的Hedgehog/GLI1和Wnt/β-catenin通路

IF 3.3 4区 医学 Q2 HEMATOLOGY
Yan Han, Chuntuan Li, Shengquan Liu, Jingjing Gao, Yanjun He, Huifang Xiao, Qi Chen, Yan Zheng, Hongyuan Chen, Xiongpeng Zhu
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引用次数: 0

摘要

套细胞淋巴瘤(MCL)是一种罕见的侵袭性非霍奇金淋巴瘤。其治疗面临的挑战包括复发、耐药性和生存期短。Hedgehog/GLI1(Hh/GLI1)和Wnt/β-catenin通路对癌细胞的增殖、存活和耐药性至关重要,因此成为抗癌研究的重要靶点。本研究旨在评估两种通路抑制剂联合使用对MCL的疗效,并研究其潜在的分子机制。在MCL中观察到Hh/GLI1和Wnt/β-catenin通路的关键蛋白共同表达。利用GLI1抑制剂GANT61靶向Hh/GLI1通路,利用CBP/β-catenin转录抑制剂ICG-001靶向Wnt/β-catenin通路,双靶向疗法被证明能协同抑制MCL细胞的活性。这种方法能促进MCL细胞凋亡,诱导G0/G1期阻滞,降低S期细胞的比例,并增强MCL细胞对阿霉素和伊布替尼药物的敏感性。GANT61和ICG-001都能下调GLI1和β-catenin,同时上调GSK-3β的表达。Hh/GLI1和Wnt/β-catenin通路之间的相互作用是由GANT61依赖的Hh/GLI1抑制介导的。此外,GLI1敲除与ICG-001联合使用可协同诱导MCL细胞凋亡,并增加其对多柔比星和伊布替尼的药物敏感性。GANT61可减轻MCL细胞中β-catenin的过表达,并降低对GSK-3β的抑制。总之,与单一疗法相比,联合靶向Hh/GLI1和Wnt/β-catenin通路能更有效地抑制MCL细胞的增殖、诱导G0/G1周期延缓、促进细胞凋亡并增加其对药物的敏感性。这些发现强调了组合疗法治疗MCL患者的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Combined targeting of Hedgehog/GLI1 and Wnt/β-catenin pathways in mantle cell lymphoma

Combined targeting of Hedgehog/GLI1 and Wnt/β-catenin pathways in mantle cell lymphoma

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Challenges in its treatment include relapse, drug resistance, and a short survival period. The Hedgehog/GLI1 (Hh/GLI1) and Wnt/β-catenin pathways are crucial in cancer cell proliferation, survival, and drug resistance, making them significant targets for anticancer research. This study aimed to assess the effectiveness of combining inhibitors for both pathways against MCL and investigate the underlying molecular mechanisms. The co-expression of key proteins from the Hh/GLI1 and Wnt/β-catenin pathways was observed in MCL. Targeting the Hh/GLI1 pathway with the GLI1 inhibitor GANT61 and the Wnt/β-catenin pathway with the CBP/β-catenin transcription inhibitor ICG-001, dual-target therapy was demonstrated to synergistically suppressed the activity of MCL cells. This approach promoted MCL cell apoptosis, induced G0/G1 phase blockade, decreased the percentage of S-phase cells, and enhanced the sensitivity of MCL cells to the drugs adriamycin and ibrutinib. Both GANT61 and ICG-001 downregulated GLI1 and β-catenin while upregulating GSK-3β expression. The interaction between Hh/GLI1 and Wnt/β-catenin pathways was mediated by GANT61-dependent Hh/GLI1 inhibition. Moreover, GLI1 knockdown combined with ICG-001 synergistically induced apoptosis and increased drug sensitivity of MCL cells to doxorubicin and ibrutinib. GANT61 attenuated the overexpression of β-catenin and decreased the inhibition of GSK-3β in MCL cells. Overall, the combined targeting of both the Hh/GLI1 and Wnt/β-catenin pathways was more effective in suppressing proliferation, inducing G0/G1 cycle retardation, promoting apoptosis, and increasing drug sensitivity of MCL cells than mono treatments. These findings emphasize the potential of combinatorial therapy for treating MCL patients.

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来源期刊
Hematological Oncology
Hematological Oncology 医学-血液学
CiteScore
4.20
自引率
6.10%
发文量
147
审稿时长
>12 weeks
期刊介绍: Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.
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