Overexpression of Mitochondrial IF1 Prevents Metastatic Disease of Colorectal Cancer by Enhancing Anoikis and Tumor Infiltration of NK Cells

Abstract

Increasing evidences show that the ATPase Inhibitory Factor 1 (IF1), the physiological inhibitor of the ATP synthase, is overexpressed in a large number of carcinomas contributing to metabolic reprogramming and cancer progression. Herein, we show that in contrast to the findings in other carcinomas, the overexpression of IF1 in a cohort of colorectal carcinomas (CRC) predicts less chances of disease recurrence, IF1 being an independent predictor of survival. Bioinformatic and gene expression analyses of the transcriptome of colon cancer cells with differential expression of IF1 indicate that cells overexpressing IF1 display a less aggressive behavior than IF1 silenced (shIF1) cells. Proteomic and functional in vitro migration and invasion assays confirmed the higher tumorigenic potential of shIF1 cells. Moreover, shIF1 cells have increased in vivo metastatic potential. The higher metastatic potential of shIF1 cells relies on increased cFLIP-mediated resistance to undergo anoikis after cell detachment. Furthermore, tumor spheroids of shIF1 cells have an increased ability to escape from immune surveillance by NK cells. Altogether, the results reveal that the overexpression of IF1 acts as a tumor suppressor in CRC with an important anti-metastatic role, thus supporting IF1 as a potential therapeutic target in CRC.

Coordinate β-adrenergic inhibition of mitochondrial activity and angiogenesis arrest tumor growth

“…Remarkably, the overexpression of IF1 in hepatocarcinomas 48 , gastric 49 , lung 50 and bladder 51 carcinomas and gliomas 52 identifies patients with worst prognosis because IF1 favors proliferation and metastatic disease. In contrast, the overexpression of IF1 in colon and breast carcinomas correlates with better patients’ prognosis 16 , 53 , stressing the importance and tissue-specific relevance of IF1 as a biomarker and target of cancer chemotherapy. Interestingly, the expression of IF1 in normal human tissues 27 and carcinomas 16 occurs independently of changes in the tissue availability of IF1 mRNA.…”

Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition

“…The transcriptomic analysis was performed by hybridization of total RNA extracted from the hippocampus of IF1 KO , control, and IF1 TG mice ( n = 3) onto mouse gene arrays (GE 4x44K v2 Microarray Kit, G4846A, Agilent Technologies), as previously described [ 96 ]. The hybridizations and statistical analyses were performed by the Genomics Facility at Centro Nacional de Biotecnología (Madrid, Spain).…”

“…The quantitative proteomic analysis of total hippocampal extracts of IF1 KO , control, and IF1 TG mice ( n = 2) was performed with isobaric tags for relative and absolute quantitation (iTRAQ) labeling method coupled to tandem mass spectrometry (MS/MS) as previously described [ 96 ]. In situ digestion of protein extracts, iTRAQ labeling, reverse phase-liquid chromatography-MS/MS analysis, and protein identification and quantitation were performed by the CBMSO Proteomic Facility.…”

“…The quantitative proteomic analysis of total hippocampal extracts of IF1 KO , control, and IF1 TG mice (n = 2) was performed with isobaric tags for relative and absolute quantitation (iTRAQ) labeling method coupled to tandem mass spectrometry (MS/MS) as previously described [96].…”

Neurensin‑2 promotes proliferation, invasion and migration of colorectal cancer cells via interaction with SOX12

“…Colorectal cancer (CRC) was the third most common malignant type of tumor worldwide in 2017 ( 1 – 3 ), and mainly results from metastasis ( 4 , 5 ). For advanced CRC, 5-year survival rates have been reported to be <50% in 2019 ( 6 ).…”