Grillo-Hill Bree K, Choi Changhoon, Jimenez-Vidal Maite, Barber Diane L
Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States.
Elife. 2015 Mar 20;4:e03270. doi: 10.7554/eLife.03270.
Intracellular pH (pHi) dynamics is increasingly recognized as an important regulator of a range of normal and pathological cell behaviors. Notably, increased pHi is now acknowledged as a conserved characteristic of cancers and in cell models is confirmed to increase proliferation and migration as well as limit apoptosis. However, the significance of increased pHi for cancer in vivo remains unresolved. Using Drosophila melanogaster, we show that increased pHi is sufficient to induce dysplasia in the absence of other transforming cues and potentiates growth and invasion with oncogenic Ras. Using a genetically encoded biosensor we also confirm increased pHi in situ. Moreover, in Drosophila models and clonal human mammary cells we show that limiting H(+) efflux with oncogenic Raf or Ras induces acidosis and synthetic lethality. Further, we show lethality in invasive primary tumor cell lines with inhibiting H(+) efflux. Synthetic lethality with reduced H(+) efflux and activated oncogene expression could be exploited therapeutically to restrain cancer progression while limiting off-target effects.
细胞内pH值（pHi）动态变化日益被认为是一系列正常和病理细胞行为的重要调节因子。值得注意的是，pHi升高现在被认为是癌症的一个保守特征，并且在细胞模型中已证实会增加增殖和迁移以及限制细胞凋亡。然而，pHi升高在体内对癌症的意义仍未解决。利用黑腹果蝇，我们表明在没有其他转化信号的情况下，pHi升高足以诱导发育异常，并增强致癌性Ras的生长和侵袭。使用基因编码生物传感器，我们还在原位证实了pHi升高。此外，在果蝇模型和克隆人乳腺细胞中，我们表明用致癌性Raf或Ras限制H(+)外流会诱导酸中毒和合成致死性。此外，我们显示抑制H(+)外流会导致侵袭性原发性肿瘤细胞系死亡。减少H(+)外流与激活致癌基因表达之间的合成致死性可用于治疗，以抑制癌症进展，同时限制脱靶效应。
