Functional Interaction between Responses to Lactic Acidosis and Hypoxia Regulates Genomic Transcriptional Outputs

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 2; pp. 491 - 502
• Main Authors: XIAOHU TANG, LUCAS, Joseph E, CHEN, Julia Ling-Yu, LAMONTE, Gregory, JIANLI WU, CHANGSHENG WANG, Michael, KOUMENIS, Constantinos, CHI, Jen-Tsan
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.01.2012
• Subjects: Acidity; Acidosis, Lactic - genetics; Acidosis, Lactic - metabolism; Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Amino acids; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer; Cell Hypoxia - genetics; Cell Line, Tumor; Cell survival; copy number; Data processing; DNA; Female; Gene Amplification; Gene expression; Gene Expression Regulation, Neoplastic; Genomics; Humans; Hypoxia-inducible factor 1 alpha; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis; Inflammation; Lactic acidosis; Medical sciences; Microenvironments; Oxygen; Pharmacology. Drug treatments; Protein folding; Signal Transduction; Solid tumors; Transcription; Transfection; Tumor cells; Tumor Microenvironment; Tumors; Metabolic disorder; Oxygen; Transcription; Genomics; Interaction; Genetics; Hypoxia; Acid base balance disorder; Lactic acid; Acidosis; Genome
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-11-2076

Within solid tumor microenvironments, lactic acidosis, and hypoxia each have powerful effects on cancer pathophysiology. However, the influence that these processes exert on each other is unknown. Here, we report that a significant portion of the transcriptional response to hypoxia elicited in cancer cells is abolished by simultaneous exposure to lactic acidosis. In particular, lactic acidosis abolished stabilization of HIF-1α protein which occurs normally under hypoxic conditions. In contrast, lactic acidosis strongly synergized with hypoxia to activate the unfolded protein response (UPR) and an inflammatory response, displaying a strong similarity to ATF4-driven amino acid deprivation responses (AAR). In certain breast tumors and breast tumor cells examined, an integrative analysis of gene expression and array CGH data revealed DNA copy number alterations at the ATF4 locus, an important activator of the UPR/AAR pathway. In this setting, varying ATF4 levels influenced the survival of cells after exposure to hypoxia and lactic acidosis. Our findings reveal that the condition of lactic acidosis present in solid tumors inhibits canonical hypoxia responses and activates UPR and inflammation responses. Furthermore, these data suggest that ATF4 status may be a critical determinant of the ability of cancer cells to adapt to oxygen and acidity fluctuations in the tumor microenvironment, perhaps linking short-term transcriptional responses to long-term selection for copy number alterations in cancer cells.