Damiano J S, Cress A E, Hazlehurst L A, Shtil A A, Dalton W S
H. Lee. Moffitt Cancer Center, University of South Florida, Tampa, FL; and the Arizona Cancer Center, University of Arizona, Tucson, AZ.
Blood. 1999 Mar 1;93(5):1658-67.
Integrin-mediated adhesion influences cell survival and may prevent programmed cell death. Little is known about how drug-sensitive tumor cell lines survive initial exposures to cytotoxic drugs and eventually select for drug-resistant populations. Factors that allow for cell survival following acute cytotoxic drug exposure may differ from drug resistance mechanisms selected for by chronic drug exposure. We show here that drug-sensitive 8226 human myeloma cells, demonstrated to express both VLA-4 (alpha4beta1) and VLA-5 (alpha5beta1) integrin fibronectin (FN) receptors, are relatively resistant to the apoptotic effects of doxorubicin and melphalan when pre-adhered to FN and compared with cells grown in suspension. This cell adhesion mediated drug resistance, or CAM-DR, was not due to reduced drug accumulation or upregulation of anti-apoptotic Bcl-2 family members. As determined by flow cytometry, myeloma cell lines selected for drug resistance, with either doxorubicin or melphalan, overexpress VLA-4. Functional assays revealed a significant increase in alpha4-mediated cell adhesion in both drug-resistant variants compared with the drug-sensitive parent line. When removed from selection pressure, drug-resistant cell lines reverted to a drug sensitive and alpha4-low phenotype. Whether VLA-4-mediated FN adhesion offers a survival advantage over VLA-5-mediated adhesion remains to be determined. In conclusion, we have demonstrated that FN-mediated adhesion confers a survival advantage for myeloma cells acutely exposed to cytotoxic drugs by inhibiting drug-induced apoptosis. This finding may explain how some cells survive initial drug exposure and eventually express classical mechanisms of drug resistance such as MDR1 overexpression.
整合素介导的黏附作用影响细胞存活，并可能阻止程序性细胞死亡。对于药物敏感的肿瘤细胞系如何在初次接触细胞毒性药物后存活下来并最终选择出耐药群体，我们了解得还很少。急性细胞毒性药物暴露后允许细胞存活的因素可能与慢性药物暴露所选择的耐药机制不同。我们在此表明，经证实表达VLA-4（α4β1）和VLA-5（α5β1）整合素纤连蛋白（FN）受体的药物敏感的8226人骨髓瘤细胞，在预先黏附于FN时，与悬浮培养的细胞相比，对阿霉素和美法仑的凋亡作用具有相对抗性。这种细胞黏附介导的耐药性，即CAM-DR，并非由于药物积累减少或抗凋亡Bcl-2家族成员的上调。通过流式细胞术测定，用阿霉素或美法仑选择出的耐药骨髓瘤细胞系中，VLA-4过表达。功能分析显示，与药物敏感的亲代细胞系相比，两种耐药变体中α4介导的细胞黏附均显著增加。当去除选择压力时耐药细胞系恢复为药物敏感且α4低表达的表型。VLA-4介导的FN黏附是否比VLA-5介导的黏附提供生存优势仍有待确定。总之，我们已经证明FN介导的黏附通过抑制药物诱导的凋亡，为急性暴露于细胞毒性药物的骨髓瘤细胞提供了生存优势。这一发现可能解释了一些细胞如何在初次药物暴露后存活下来，并最终表达经典的耐药机制，如MDR1过表达。
