Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers

Abstract

Recent findings in colon cancer cells indicate that inhibition of the mitochondrial H+-adenosine triphosphate (ATP) synthase by the ATPase inhibitory factor 1 (IF1) promotes aerobic glycolysis and a reactive oxygen species (ROS)-mediated signal that enhances proliferation and cell survival. Herein, we have studied the expression, biological relevance, mechanism of regulation and potential clinical impact of IF1 in some prevalent human carcinomas. We show that IF1 is highly overexpressed in most (>90%) of the colon (n=64), lung (n=30), breast (n=129) and ovarian (n=10) carcinomas studied as assessed by different approaches in independent cohorts of cancer patients. The expression of IF1 in the corresponding normal tissues is negligible. By contrast, the endometrium, stomach and kidney show high expression of IF1 in the normal tissue revealing subtle differences by carcinogenesis. The overexpression of IF1 also promotes the activation of aerobic glycolysis and a concurrent ROS signal in mitochondria of the lung, breast and ovarian cancer cells mimicking the activity of oligomycin. IF1-mediated ROS signaling activates cell-type specific adaptive responses aimed at preventing death in these cell lines. Remarkably, regulation of IF1 expression in the colon, lung, breast and ovarian carcinomas is exerted at post-transcriptional levels. We demonstrate that IF1 is a short-lived protein (t1/2 ∼100 min) strongly implicating translation and/or protein stabilization as main drivers of metabolic reprogramming and cell survival in these human cancers. Analysis of tumor expression of IF1 in cohorts of breast and colon cancer patients revealed its relevance as a predictive marker for clinical outcome, emphasizing the high potential of IF1 as therapeutic target.

RETRACTED: ATPase inhibitory factor 1 is a prognostic marker and contributes to proliferation and invasion of human gastric cancer cells

“…IF1 has been considered as an inhibitor for the activity of the mitochondrial H + -ATP synthase [10]. Elevated IF1 expression is observed in a number of human cancers, such as colon cancer [11], lung cancer [12], breast cancer [12], ovarian cancer [12] and hepatocellular carcinoma (HCC) [13]. IF1 is an antiapoptotic and potentially tumorigenic factor and may be a valuable predictor of responsiveness to chemotherapy [9].…”

Silencing of ATPase Inhibitory Factor 1 Inhibits Cell Growth via Cell Cycle Arrest in Bladder Cancer

“…It has unique capacity to inhibit the hydrolase activity of F 1 F o -ATP synthase, which is its reverse role. IF1 is known to play a major role in heme biosynthesis and mitochondrial respiratory chain dysfunction [3,18], and, moreover, has been linked to different cancer types [8,9,10,19,20]. Although IF1 has been associated with tumor activity [3,6,7], IF1 has not been associated with specific changes in the cell cycle previously.…”

“…But other reports claim that a low tumor expression of IF1 predicts the worst prognosis overall for breast and colon cancer patients [10]. These results suggest that the functional effect of IF1 in human tumors is complicated.…”

Metabolic control of cancer cell stemness: Lessons from iPS cells

“…Also, iPS cells drastically limit the activity and cellular content of the mitochondrial H C -ATPase synthase, a molecular feature that correlates directly with OXPHOS activity and inversely with the rate of glucose utilization by aerobic glycolysis in tumor tissues. [51][52][53][54][55][56][57][58][59] Somatic cell reprogramming involves a dramatic downregulation of the catalytic b1-F1-ATPase subunit and a significant increase in the expression of ATPase inhibitor factor 1 (IF1), a marker that is expressed in adult stem cells (ASC) for maintaining the activity of aerobic glycolysis, but is not expressed in equivalent differentiated cells. 60 Although little is known about the bioenergetic resetting of CSC, it appears that analogous to iPS cells, a direct link might exist between the occurrence of a metabolic switch from OXPHOS to aerobic glycolysis and the occurrence and maintenance of CSC cellular states.…”