Johnstone R W, Tainton K M, Ruefli A A, Froelich C J, Cerruti L, Jane S M, Smyth M J
Peter MacCallum Cancer Institute, Trescowthick Research Laboratories, St. Andrews Place, East Melbourne 3002, Victoria, Australia.
J Biol Chem. 2001 May 18;276(20):16667-73. doi: 10.1074/jbc.M010774200. Epub 2001 Feb 20.
P-glycoprotein (P-gp) is an ATP-dependent drug pump that confers multidrug resistance (MDR). In addition to its ability to efflux toxins, P-gp can also inhibit apoptosis induced by a wide array of cell death stimuli that rely on activation of intracellular caspases for full function. We therefore hypothesized that P-gp may have additional functions in addition to its role in effluxing xenotoxins that could provide protection to tumor cells against a host response. There have been a number of contradictory reports concerning the role of P-gp in regulating complement activation. Given the disparate results obtained by different laboratories and our published results demonstrating that P-gp does not affect cell death induced by another membranolytic protein, perforin, we decided to assess the role of P-gp in regulating cell lysis induced by a number of different pore-forming proteins. Testing a variety of different P-gp-expressing MDR cell lines produced following exposure of cells to chemotherapeutic agents or by retroviral gene transduction in the complete absence of any drug selection, we found no difference in sensitivity of P-gp(+ve) or P-gp(-ve) cells to the pore-forming proteins complement, perforin, or pneumolysin. Based on these results, we conclude that P-gp does not affect cell lysis induced by pore-forming proteins.
P-糖蛋白（P-gp）是一种依赖ATP的药物泵，可赋予多药耐药性（MDR）。除了具有排出毒素的能力外，P-gp还能抑制由多种细胞死亡刺激诱导的凋亡，这些刺激依赖细胞内半胱天冬酶的激活来发挥全部功能。因此，我们推测P-gp除了在排出外源性毒素方面发挥作用外，可能还具有其他功能，从而为肿瘤细胞提供针对宿主反应的保护。关于P-gp在调节补体激活中的作用，已有许多相互矛盾的报道。鉴于不同实验室得到的结果存在差异，以及我们已发表的结果表明P-gp不影响另一种膜溶解蛋白穿孔素诱导的细胞死亡，我们决定评估P-gp在调节多种不同成孔蛋白诱导的细胞裂解中的作用。我们测试了多种不同的表达P-gp的多药耐药细胞系，这些细胞系是在细胞暴露于化疗药物后产生的，或者是通过逆转录病毒基因转导产生的，且完全没有任何药物选择，我们发现P-gp（阳性）或P-gp（阴性）细胞对成孔蛋白补体、穿孔素或肺炎链球菌溶血素的敏感性没有差异。基于这些结果，我们得出结论，P-gp不影响成孔蛋白诱导的细胞裂解。
