ABSTRACT Certain cancer types, including breast cancer, are accompanied with stiffening of the surrounding extracellular matrix (ECM). Previous studies suggest that this stiffened matrix influences cancer cell progression, such as proliferation and invasion, both biochemically and mechanically. However, the contribution of ECM stiffness to cellular response to diverse stresses, which most cancer cells are exposed to, has not been elucidated. In this study, we demonstrate that expression of the Shwachman-Bodian-Diamond syndrome protein (SDBS) in a stiff matrix protects cells from apoptosis induced by environmental stress, including anticancer drugs. Cells cultured on stiff matrices were less apoptotic process induced by serum depletion than those cultured on the soft matrix. Interestingly, knockdown (KD) of SDBS among the apoptosis-related genes significantly increased apoptosis induced by serum depletion in cells cultured in a stiff matrix. Apoptosis of SDBS KD cells in a stiff matrix was significantly inhibited by the caspase 8 inhibitor, indicating that activation of the caspase 8 pathway by SDBS KD is critical for cancer cell apoptosis in stiff matrices. Additionally, we also found that downregulation of SDBS also effectively increased cell death induced by anticancer drugs, including paclitaxel, cisplatin, and eribulin. Taken together, our findings suggest that inhibition of SDBS enhances effective chemotherapy of malignant breast cancer cells in stiff ECM environments.

中文翻译：

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Shwachman-Bodian-Diamond 综合征蛋白通过抑制半胱天冬酶 8 介导的通路使乳腺癌细胞对僵硬基质中的细胞凋亡脱敏

摘要某些癌症类型，包括乳腺癌，伴随着周围细胞外基质 (ECM) 的硬化。先前的研究表明，这种硬化的基质会在生化和机械方面影响癌细胞的进展，例如增殖和侵袭。然而，ECM 刚度对细胞对大多数癌细胞所暴露的各种压力的反应的贡献尚未阐明。在这项研究中，我们证明 Shwachman-Bodian-Diamond 综合征蛋白 (SDBS) 在刚性基质中的表达可保护细胞免受环境压力（包括抗癌药物）诱导的细胞凋亡。与在软基质上培养的细胞相比，在硬基质上培养的细胞由血清耗竭诱导的细胞凋亡过程较少。有趣的是，细胞凋亡相关基因中 SDBS 的敲低 (KD) 显着增加了在刚性基质中培养的细胞中血清耗竭诱导的细胞凋亡。半胱天冬酶 8 抑制剂显着抑制硬基质中 SDBS KD 细胞的凋亡，表明 SDBS KD 激活半胱天冬酶 8 通路对硬基质中的癌细胞凋亡至关重要。此外，我们还发现 SDBS 的下调也有效地增加了抗癌药物诱导的细胞死亡，包括紫杉醇、顺铂和艾日布林。总之，我们的研究结果表明，在僵硬的 ECM 环境中，SDBS 的抑制增强了恶性乳腺癌细胞的有效化疗。半胱天冬酶 8 抑制剂显着抑制硬基质中 SDBS KD 细胞的凋亡，表明 SDBS KD 激活半胱天冬酶 8 通路对硬基质中的癌细胞凋亡至关重要。此外，我们还发现 SDBS 的下调也有效地增加了抗癌药物诱导的细胞死亡，包括紫杉醇、顺铂和艾日布林。总之，我们的研究结果表明，在僵硬的 ECM 环境中，SDBS 的抑制增强了恶性乳腺癌细胞的有效化疗。半胱天冬酶 8 抑制剂显着抑制硬基质中 SDBS KD 细胞的凋亡，表明 SDBS KD 激活半胱天冬酶 8 通路对硬基质中的癌细胞凋亡至关重要。此外，我们还发现 SDBS 的下调也有效地增加了抗癌药物诱导的细胞死亡，包括紫杉醇、顺铂和艾日布林。总之，我们的研究结果表明，在僵硬的 ECM 环境中，SDBS 的抑制增强了恶性乳腺癌细胞的有效化疗。和艾日布林。总之，我们的研究结果表明，在僵硬的 ECM 环境中，SDBS 的抑制增强了恶性乳腺癌细胞的有效化疗。和艾日布林。总之，我们的研究结果表明，在僵硬的 ECM 环境中，SDBS 的抑制增强了恶性乳腺癌细胞的有效化疗。