Department of Biochemistry, National University of Singapore, 8 Medical Drive, MD7, #03-08, Singapore 117597.
Curr Med Chem. 2014;21(2):251-60. doi: 10.2174/09298673113206660269.
Drug resistance is a major hurdle to the success of chemotherapy. The permeability glycoprotein (P-gp) is an important factor dictating drug access to the cells, as it controls the efflux of chemotherapeutic agents against the concentration gradient. Pmd1, a P-gp-like protein, was recently isolated as a doxorubicin resistance gene in fission yeast. Although the null mutant of pmd1 (Δpmd1) exhibited sensitivity to doxorubicin, it showed an unexpectedly high resistance to the drug at relatively high concentrations. The data presented here suggest that this is due to the presence of cooperative processes that can complement and counteract drug cytotoxicity in the absence of Pmd1. One such factor, Rav1, is an essential factor in controlling the assembly of the pH-regulating transporter vacuolar-ATPase (V-ATPase) in fission yeast. The simultaneous disruption of Pmd1 and Rav1 resulted in a prominent accumulation of doxorubicin in the cytoplasm of cells, accompanied by a decline in cell viability. With concurrent treatment of pharmacological inhibitors in human cervical cancer cells, P-gp and V-ATPase were further shown to act synergistically to sensitize cells to doxorubicin also in the human cells. Furthermore, a novel Cornichon-like protein SPAC2C4.05 (herein named as Cor1) was demonstrated for the first time to be involved in the interaction with P-gp and V-ATPase to counteract doxorubicin-dependent cytotoxicity. Therefore this study identified a molecular cooperation between multiple membrane transporter proteins that confers chemoresistance to cells against the chemical insult of doxorubicin. Interestingly, this network exhibited differential effects to doxorubicin as compared with its close epimeric analog epirubicin, suggestive of the intricacy of the drug response regulated by this synergistic interaction. A model is discussed on how the versatility of this network can differentiate closely related chemical drug structures yet allow for the robustness to counteract a vast range of drugs.
耐药性是化疗成功的主要障碍。 多药耐药相关蛋白（P-gp）是决定药物进入细胞的重要因素，因为它控制着化学治疗剂逆浓度梯度的外排。Pmd1 是一种 P-gp 样蛋白，最近被分离为裂殖酵母中阿霉素耐药基因。尽管 pmd1 的缺失突变体（Δpmd1）对阿霉素敏感，但在相对较高的浓度下，它出人意料地对该药物表现出高耐药性。这里提供的数据表明，这是由于存在协同过程所致，这些过程可以在没有 Pmd1 的情况下补充和抵消药物的细胞毒性。 其中一个因素 Rav1 是裂殖酵母 pH 调节转运体液泡型 ATP 酶（V-ATPase）组装的必需因素。Pmd1 和 Rav1 的同时破坏导致阿霉素在细胞细胞质中的明显积累，同时细胞活力下降。在人宫颈癌细胞中同时用药理抑制剂处理时，还进一步表明 P-gp 和 V-ATPase 协同作用可使细胞对阿霉素敏感。此外，首次证明一种新型 Cornichon 样蛋白 SPAC2C4.05（在此命名为 Cor1）参与与 P-gp 和 V-ATPase 的相互作用，以抵消阿霉素依赖性细胞毒性。因此，本研究鉴定了多个膜转运蛋白之间的分子协同作用，该协同作用赋予了细胞对阿霉素的化学刺激的抗药性。有趣的是，与阿霉素的近对映体表阿霉素相比，该网络对阿霉素的作用表现出不同的效果，提示该协同作用调节的药物反应的复杂性。讨论了一个模型，说明该网络的多功能性如何区分密切相关的化学药物结构，同时允许对抗广泛的药物。
