CD49d and CD49e induce cell adhesion-mediated drug resistance through the nuclear factor-κB pathway in Burkitt lymphoma.
CD49d and CD49e induce cell adhesion-mediated drug resistance through the nuclear factor-κB pathway in Burkitt lymphoma.
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DOI：
10.26402/jpp.2020.4.02
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发表时间：
2020-08
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影响因子：
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通讯作者：
T. Takeda;M. Tsubak;S. Genno;T. Matsuda;Y. Yamamoto;E. Ueda;M. Imano;T. Satou;S. Nishida
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文献类型：
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作者：
T. Takeda;M. Tsubak;S. Genno;T. Matsuda;Y. Yamamoto;E. Ueda;M. Imano;T. Satou;S. Nishida
伯基特淋巴瘤是一种高度侵袭性的非霍奇金B细胞淋巴瘤。目前，多药物化疗方案正被用于显著提高白血病患者的治愈率并实现完全缓解。然而，在BL患者中，耐药通常在6个月内发生，导致预后不良。越来越多的证据表明，骨髓微环境与肿瘤细胞相互作用引起的细胞黏附介导的耐药(CAM-DR)可能在化疗耐药中起重要作用。然而，目前尚不清楚大脑皮层细胞间黏附分子-DR的分子机制。在这项研究中，我们研究了在BL细胞中引起CAM-DR的分子机制。我们还检测了CAM-DR在BL细胞中的治疗靶点，发现CD49d和CD49e是参与其中的重要黏附分子。但未发现CD49a、CD49b、CD11a、CD29、CD18和CD61与白血病细胞中的CAM-DR相关。我们进一步阐明CD49d和CD49e介导的细胞间黏附分子-DR可能与B细胞白血病-XL(BclXL)和Survivin蛋白表达增加有关，而Bcl2相关X(BAX)、Bcl2相互作用介体(Bim)和P53上调的凋亡调节因子(PUMA)蛋白的表达则通过核因子κB的激活而减少。此外，我们还发现Bortezomib通过抑制NF-κB而克服了BL细胞中的CAM-DR。因此，Bortezomib可能在治疗由CD49d和CD49e介导的BL患者的CAM-DR方面具有潜在的临床应用价值。
Burkitt lymphoma (BL) is a highly aggressive form of non-Hodgkin's B-cell lymphoma. Currently, multi-agent chemotherapy regimens are being used to significantly improve cure rates and achieve complete remissions in BL patients. However, drug resistance can often occur within 6 months in BL patients, contributing to poor prognosis. Mounting evidence suggests that cell adhesion-mediated drug resistance (CAM-DR), caused by the interaction between the bone marrow microenvironment and tumour cells may play an important role in drug resistance to chemotherapy. However, the molecular mechanism underlying CAM-DR in BL has not been identified yet. In this study, we investigated the molecular mechanism responsible for CAM-DR in BL cells. We also examined the therapeutic targets of CAM-DR in BL cells and found CD49d and CD49e to be the important adhesion molecules involved. However, CD49a, CD49b, CD11a, CD29, CD18, and CD61 were not found to be associated with CAM-DR in BL cells. Furthermore, we clarified that CD49d- and CD49e-mediated CAM-DR could be attributed to an increase in the expression of B cell leukemia-xL (Bcl-xL) and survivin proteins, and a decrease in the expression of Bcl-2 associated X (Bax), Bcl-2 interacting mediator (Bim) and p53 upregulated modulator of apoptosis (PUMA) proteins via nuclear factor kappaB (NF-κB) activation. In addition, bortezomib was found to overcome CAM-DR in BL cells by inhibiting NF-κB. Thus, bortezomib may have potential clinical applications in the treatment of CD49d- and CD49e-mediated CAM-DR in BL patients.