Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and γ-irradiation
Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and γ-irradiation
复制标题
DOI：
10.1038/sj.leu.2402179
复制
发表时间：
2001-08-01
期刊：
影响因子：
11.4
通讯作者：
Dalton, WS
中科院分区：
文献类型：
--
作者：
Damiano, JS;Hazlehurst, LA;Dalton, WS
整合素介导的细胞与细胞外基质（ECM）成分的粘附是人骨髓瘤细胞化疗反应的重要决定因素。在这里，我们证明，当K562慢性粒细胞白血病（CML）细胞粘附到纤连蛋白（FN），他们成为耐凋亡诱导的BCR/ABL抑制剂AG 957和STI-571，以及DNA损伤剂和γ-射线。这种现象被称为细胞粘附介导的耐药性（CAM-DR），是通过α 5 β 1（VLA-5）整合素的粘附诱导的。磷酸酪氨酸分析表明，通过整合素在K562细胞中的抗凋亡信号是独立的酪氨酸激酶激活的BCR/ABL，与一个未知的80 kDa蛋白质的可能例外。FN粘附的CML细胞的细胞保护作用表明肿瘤-ECM相互作用可能对这种疾病中耐药肿瘤群体的出现和治疗失败至关重要。β 1整联蛋白介导的粘附或相应的信号转导元件的拮抗剂可以使CML细胞对化疗敏感，并防止对用于治疗这种疾病的新型BCR/ABL激酶抑制剂的耐药性。
Integrin-mediated cellular adhesion to extracellular matrix (ECM) components is an important determinant of chemotherapeutic response of human myeloma cells. Here, we demonstrate that when K562 chronic myelogenous leukemia (CML) cells are adhered to fibronectin (FN), they become resistant Ito apoptosis induced by the BCR/ABL inhibitors AG957 and STI-571, as well as DNA damaging agents and gamma -irradiation. This phenomenon, termed cell adhesion-mediated drug resistance (CAM-DR), was induced by adhesion through the alpha5 beta1 (VLA-5) integrin. Phosphotyrosine analysis demonstrates that anti-apoptotic signaling through integrins in K562 cells is independent of the tyrosine kinases activated by BCR/ABL, with the possible exception of an unknown 80 kDa protein. Cytoprotection of FN-adhered CML cells indicates that tumor-ECM interactions may be critical for the emergence of drug-resistant tumor populations and treatment failure in this disease. Antagonists of beta1 integrin-mediated adhesion or corresponding signal transduction elements may sensitize CML cells to chemotherapy and prevent resistance to the novel BCR/ABL kinase inhibitors being used for the treatment of this disease.