Central role of lactic acidosis in cancer cell resistance to glucose deprivation-induced cell death

• Published in: The Journal of pathology Vol. 227; no. 2; pp. 189 - 199
• Main Authors: Wu, Hao, Ding, Zonghui, Hu, Danqing, Sun, Feifei, Dai, Chunyan, Xie, Jiansheng, Hu, Xun
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.06.2012; Wiley
• Subjects: Acidosis, Lactic - genetics; Acidosis, Lactic - metabolism; Acidosis, Lactic - pathology; Animals; Apoptosis; Autophagy; Biological and medical sciences; cell cycle; Cell Line, Tumor; Cell Survival; G1 Phase Cell Cycle Checkpoints; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Glucose - deficiency; glucose deprivation; Humans; Hydrogen-Ion Concentration; Investigative techniques, diagnostic techniques (general aspects); lactic acidosis; Medical sciences; Mice; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Oligonucleotide Array Sequence Analysis; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Time Factors; Tumor Microenvironment; lactic acidosis; Acid base balance disorder; Glucose; Autophagy; Resistance; Metabolic disorder; Anatomic pathology; Cell death; Cell cycle; Lactic acid; Acidosis; Tumor cell; Apoptosis; glucose deprivation
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.3978

Solid tumours are dependent on glucose, but are generally glucose‐deprived due to poor vascularization. Nevertheless, cancer cells can generally survive glucose deprivation better than their normal counterparts. Thus, to render cancer cells sensitive to glucose depletion may potentially provide an effective strategy for cancer intervention. We propose that lactic acidosis, a tumour microenvironment factor, may allow cancer cells to develop resistance to glucose deprivation‐induced death, and that disruption of lactic acidosis may resume cancer cells' sensitivity to glucose depletion. Lactic acidosis, lactosis, or acidosis was generated by adding pure lactic acid, sodium lactate, or HCl to the culture medium. Cell death, cell cycle, autophagy, apoptosis, and gene expression profiling of the surviving cancer cells under glucose deprivation with lactic acidosis were determined. Under glucose deprivation without lactic acidosis, 90% of 4T1 cancer cells died within a single day; in a sharp contrast, under lactic acidosis, 90% of 4T1 cells died in a period of 10 days, with viable cells identified even 65 days after glucose was depleted. Upon glucose restoration, surviving cells resumed proliferation. Lactic acidosis also significantly extended survival of other cancer cells under glucose deprivation. G1/G0 arrest, autophagy induction, and apoptosis inhibition were tightly associated with lactic acidosis‐mediated resistance to glucose deprivation. Lactosis alone had no effect on cell survival under glucose deprivation; acidosis alone can prolong cell survival time but is not as potent as lactic acidosis. Thus, the ability of cancer cells to resist glucose deprivation‐induced cell death is conferred, at least in part, by lactic acidosis, and we envision that disrupting the lactic acidosis may resume the sensitivity of cancer cells to glucose deprivation. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.