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Interactions of Aldolase A with ATPase Inhibitory Factor 1 Reprogram Energy Metabolism to Maintain Cancer Stemness
Author(s) -
Chang YuChan,
Hsiao Michael
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.496.6
Subject(s) - aldolase a , glycolysis , warburg effect , anaerobic glycolysis , cancer cell , biology , carcinogenesis , cancer , cancer research , microbiology and biotechnology , phosphoglycerate mutase , cancer stem cell , biochemistry , stem cell , enzyme , genetics
Cancer cells utilize glycolysis for the production of ATP and metabolic reprogramming (Warburg effect), as opposed to differentiated bulk tumor cells relying on glycolysis. Cancer Stem cells (CSCs) showed a distinct metabolic phenotype that, depending on the cancer type, could be highly glycolytic or rely on an OXPHOS‐dependent pathway. Aldolase A (ALDOA) has been regarded as one of the key enzymes involved in glycolysis. Overexpression of ALDOA correlated with cancer proliferation and metastasis, and formed a positive feedback loop with HIF‐1alpha during tumorigenesis. Through mass spectrometry‐based ALDOA interactive proteomic database analysis, we have discovered that ALDOA binds directly to ATPase inhibitory factor 1 (IF1). ATPIF1 is a physiological inhibitor of H + ‐ATP synthase that is highly overexpressed in the mitochondria of cancer cells. Overexpression of IF1 results in the inhibition of ATP synthesis by the enzyme and a switch to increased aerobic glycolysis and increased ROS‐mediated signaling related to several features of the oncogenic phenotype. We further identified ATPIF1 could be degraded after binding to ALDOA and this function could be rescued by the addition of proteasome inhibitor. In addition, ATP5 family members were found to be upregulated with or without ALDOA enzymatic activity to maintain cancer stemness phenotypes in various types of cancer cells. The additions of IFA could significantly reverse the ALDOA‐induced cancer stemness in a dose‐dependent manner. Moreover, we observed the inverse RNA and protein expression correlations of ALDOA and ATPIF1 predict significant poor prognosis in many clinical cohorts including gliomas, lung and colon cancers. In conclusions, our results provided evidences that ALDOA binding ATPIF1 induce its degradation to modulate energy reprogramming controls and maintain cancer stemness in human cancer cells. This niche may allow new target‐drug development by aiming at the inhibition of ALDOA/IF1 protein binding to suppress cancer stemness. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .