Department of Translational Medicine, Lund University, Malmö, S-214 28, Sweden.
Department of Microbiology, Saitama Medical University, Saitama, 350-0495, Japan.
Cell Death Dis. 2024 Jul 4;15(7):480. doi: 10.1038/s41419-024-06872-7.
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.
化疗仍然是乳腺癌的主要治疗方法，但化疗耐药性是成功治疗的主要障碍。在此，我们表明软骨寡聚基质蛋白（COMP）的表达导致在几种化疗药物、抗 HER2 靶向治疗和内分泌治疗下，在测试的几种乳腺癌细胞系中，癌细胞存活增加和凋亡减少。COMP 诱导的化疗耐药性与乳腺癌亚型无关。细胞外给予重组 COMP 不能挽救细胞免于凋亡，而内质网（ER）限制的 COMP-KDEL 赋予细胞对凋亡的抗性，这与 COMP 在 ER 中的定位一致，在 ER 中它与钙蛋白酶相互作用。钙蛋白酶在 COMP 表达细胞中的活性降低，在用表柔比星治疗时保持在较低的激活水平。此外，钙蛋白酶的下游半胱天冬酶 -9、-7 和 -3 在化疗处理下在 COMP 表达细胞中表现出明显降低的激活。化疗与钙蛋白酶激活剂联合使用，使表达 COMP 的细胞对化疗更敏感。此外，在化疗时，表达 COMP 的细胞中磷酸化 Bcl2 和存活素等抗凋亡蛋白增加。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疗耐药性。评估 ER、细胞质和线粒体中的钙水平表明，COMP 表达调节细胞内钙稳态。此外，在接受化疗或内分泌治疗的患者中，当肿瘤表达高水平的 COMP 时，其总生存时间明显缩短。这项研究确定了 COMP 在乳腺癌中的化疗耐药性和钙蛋白酶失活中的新作用，这一发现可能对癌症治疗具有重要意义。
