Nguyen Thi Thuy Trang, Lim Ying Jun, Fan Melanie Hui Min, Jackson Rebecca A, Lim Kim Kiat, Ang Wee Han, Ban Kenneth Hon Kim, Chen Ee Sin
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
National University Health System, Singapore.
Genes Cells. 2016 Mar;21(3):226-40. doi: 10.1111/gtc.12346. Epub 2016 Feb 18.
Doxorubicin is a widely used chemotherapeutic agent, but its utility is limited by cellular resistance and off-target effects. To understand the molecular mechanisms regulating chemotherapeutic responses to doxorubicin, we previously carried out a genomewide search of doxorubicin-resistance genes in Schizosaccharomyces pombe fission yeast and showed that these genes are organized into networks that counteract doxorubicin cytotoxicity. Here, we describe the identification of a subgroup of doxorubicin-resistance genes that, when disrupted, leads to reduced tolerance to exogenous calcium. Unexpectedly, we observed a suppressive effect of calcium on doxorubicin cytotoxicity, where concurrent calcium and doxorubicin treatment resulted in significantly higher cell survival compared with cells treated with doxorubicin alone. Conversely, inhibitors of voltage-gated calcium channels enhanced doxorubicin cytotoxicity in the mutants. Consistent with these observations in fission yeast, calcium also suppressed doxorubicin cytotoxicity in human breast cancer cells. Further epistasis analyses in yeast showed that this suppression of doxorubicin toxicity by calcium was synergistically dependent on Rav1 and Vph2, two regulators of vacuolar-ATPase assembly; this suggests potential modulation of the calcium-doxorubicin interaction by fluctuating proton concentrations within the cellular environment. Thus, the modulatory effects of drugs or diet on calcium concentrations should be considered in doxorubicin treatment regimes.
阿霉素是一种广泛使用的化疗药物，但其效用受到细胞耐药性和脱靶效应的限制。为了了解调节对阿霉素化疗反应的分子机制，我们之前在粟酒裂殖酵母中进行了全基因组范围内的阿霉素耐药基因搜索，并表明这些基因组织成网络以对抗阿霉素的细胞毒性。在此，我们描述了一组阿霉素耐药基因的鉴定，当这些基因被破坏时，会导致对外源钙的耐受性降低。出乎意料的是，我们观察到钙对阿霉素细胞毒性有抑制作用，与单独用阿霉素处理的细胞相比，同时进行钙和阿霉素处理会导致细胞存活率显著更高。相反，电压门控钙通道抑制剂增强了突变体中阿霉素的细胞毒性。与在裂殖酵母中的这些观察结果一致，钙在人乳腺癌细胞中也抑制了阿霉素的细胞毒性。酵母中的进一步上位性分析表明，钙对阿霉素毒性的这种抑制作用协同依赖于液泡 - ATP 酶组装的两个调节因子 Rav1 和 Vph2；这表明细胞环境中质子浓度的波动可能对钙 - 阿霉素相互作用有潜在调节作用。因此，在阿霉素治疗方案中应考虑药物或饮食对钙浓度的调节作用。
