化疗仍然是乳腺癌的主要干预措施,化学耐药性是成功治疗的主要障碍。在这里,我们表明,软骨寡聚基质蛋白(COMP)的表达导致增加的癌细胞存活和减少凋亡治疗的几种化疗药物,抗HER2靶向治疗,和内分泌治疗在几个乳腺癌细胞系测试。COMP诱导的化疗耐药与乳腺癌亚型无关。细胞外递送的重组COMP未能挽救细胞凋亡,而内质网(ER)限制的COMP-KDEL赋予细胞凋亡抗性,与COMP在ER中的本地化一致,它和钙蛋白酶相互作用的地方。在表达COMP的细胞中,钙蛋白酶的活化降低,并在表柔比星治疗期间维持在较低的活化水平。此外,钙蛋白酶的下游半胱天冬酶,caspases-9、-7和-3在化学疗法处理下在表达COMP的细胞中表现出显著降低的活化。化疗,当与钙蛋白酶激活剂结合使用时,使表达COMP的细胞更化学敏感。此外,抗凋亡蛋白磷酸化-Bcl2和survivin在化疗后表达COMP的细胞中增加.与表达全长COMP的细胞相比,表达缺乏血小板反应蛋白重复的突变型COMP的细胞表现出降低的化学抗性。评估ER中的钙水平,胞质溶胶,线粒体显示COMP表达调节细胞内钙稳态。此外,当肿瘤表达高水平的COMP时,接受化疗或内分泌治疗的患者的总生存期显著缩短.这项研究确定了COMP在乳腺癌化疗耐药和钙蛋白酶失活中的新作用。对抗癌治疗有潜在影响的发现。
Chemotherapy persists as the primary intervention for breast cancer, with chemoresistance posing the principal obstacle to successful treatment. Herein, we show that cartilage oligomeric matrix protein (COMP) expression leads to increased cancer cell survival and attenuated apoptosis under treatment with several chemotherapeutic drugs, anti-HER2 targeted treatment, and endocrine therapy in several breast cancer cell lines tested. The COMP-induced chemoresistance was independent of the breast cancer subtype. Extracellularly delivered recombinant COMP failed to rescue cells from apoptosis while endoplasmic reticulum (ER)-restricted COMP-KDEL conferred resistance to apoptosis, consistent with the localization of COMP in the ER, where it interacted with
calpain.
Calpain activation was reduced in COMP-expressing cells and maintained at a lower level of activation during treatment with epirubicin. Moreover, the downstream caspases of
calpain, caspases -9, -7, and -3, exhibited significantly reduced activation in COMP-expressing cells under chemotherapy treatment. Chemotherapy, when combined with
calpain activators, rendered the cells expressing COMP more chemosensitive. Also, the anti-apoptotic proteins phospho-Bcl2 and survivin were increased in COMP-expressing cells upon chemotherapy. Cells expressing a mutant COMP lacking thrombospondin repeats exhibited reduced chemoresistance compared to cells expressing full-length COMP. Evaluation of calcium levels in the ER, cytosol, and mitochondria revealed that COMP expression modulates intracellular calcium homeostasis. Furthermore, patients undergoing chemotherapy or endocrine therapy demonstrated significantly reduced overall survival time when tumors expressed high levels of COMP. This study identifies a novel role of COMP in chemoresistance and
calpain inactivation in breast cancer, a discovery with potential implications for anti-cancer therapy.