Acquired multidrug resistance of cancer cells challenges the chemotherapeutic interventions. To understand the role of molecular chaperone, Hsp90 in drug adapted tumor cells, we have used in vitro drug adapted epidermoid tumor cells as a model system. We found that chemotherapeutic drug adaptation of tumor cells is mediated by induced activities of both Hsp90 and P-glycoprotein (P-gp). Although the high-affinity conformation of Hsp90 has correlated with the enhanced drug efflux activity, we did not observe a direct interaction between P-gp and Hsp90. The enrichment of P-gp and Hsp90 at the cholesterol-rich membrane microdomains is found obligatory for enhanced drug efflux activity. Since inhibition of cholesterol biosynthesis is not interfering with the drug efflux activity, it is presumed that the net cholesterol redistribution mediated by Hsp90 regulates the enhanced drug efflux activity. Our in vitro cholesterol and Hsp90 interaction studies have furthered our presumption that Hsp90 facilitates cholesterol redistribution. The drug adapted cells though exhibited anti-proliferative and anti-tumor effects in response to 17AAG treatment, drug treatment has also enhanced the drug efflux activity. Our findings suggest that drug efflux activity and metastatic potential of tumor cells are independently regulated by Hsp90 by distinct mechanisms. We expose the limitations imposed by Hsp90 inhibitors against multidrug resistant tumor cells.

中文翻译：

---

Hsp90通过胆固醇调节促进肿瘤细胞获得性耐药，但与肿瘤进展无关。

获得性的癌细胞多药耐药性挑战了化学疗法的干预。为了了解分子伴侣蛋白Hsp90在药物适应性肿瘤细胞中的作用，我们使用了体外药物适应性表皮样肿瘤细胞作为模型系统。我们发现肿瘤细胞的化疗药物适应性是由Hsp90和P-糖蛋白（P-gp）的诱导活性介导的。尽管Hsp90的高亲和力构象与增强的药物外排活性相关，但我们没有观察到P-gp和Hsp90之间的直接相互作用。发现在富含胆固醇的膜微域中P-gp和Hsp90的富集对于增强药物外排活性是必不可少的。由于抑制胆固醇的生物合成不会干扰药物的外排活性，据推测，由Hsp90介导的净胆固醇重新分布调节了增强的药物外排活性。我们的体外胆固醇和Hsp90相互作用研究进一步推定了Hsp90促进胆固醇重新分布的推测。适应药物的细胞虽然响应于17AAG治疗表现出抗增殖和抗肿瘤作用，但是药物治疗也增强了药物外排活性。我们的发现表明，Hsp90通过不同的机制独立调节药物的流出活性和肿瘤细胞的转移潜能。我们揭露了Hsp90抑制剂对多药耐药肿瘤细胞的局限性。适应药物的细胞虽然响应于17AAG治疗表现出抗增殖和抗肿瘤作用，但是药物治疗也增强了药物外排活性。我们的发现表明，Hsp90通过不同的机制独立调节药物的流出活性和肿瘤细胞的转移潜能。我们揭露了Hsp90抑制剂对多药耐药肿瘤细胞的局限性。适应药物的细胞虽然响应于17AAG治疗表现出抗增殖和抗肿瘤作用，但是药物治疗也增强了药物外排活性。我们的发现表明，Hsp90通过不同的机制独立调节药物的流出活性和肿瘤细胞的转移潜能。我们揭露了Hsp90抑制剂对多药耐药肿瘤细胞的局限性。