Abstract
Mitochondrial transcriptional factor A (TFAM) acts as a key regulatory to control mitochondrial DNA (mtDNA); the impact of TFAM and mtDNA in modulating carcinogenesis is controversial. Current study aims to define TFAM mediated regulations in head and neck cancer (HNC). Multifaceted analyses in HNC cells genetically manipulated for TFAM were performed. Clinical associations of TFAM and mtDNA encoded Electron Transport Chain (ETC) genes in regulating HNC tumourigenesis were also examined in HNC specimens. At cellular level, TFAM silencing led to an enhanced cell growth, motility and chemoresistance whereas enforced TFAM expression significantly reversed these phenotypic changes. These TFAM mediated cellular changes resulted from (1) metabolic reprogramming by directing metabolism towards aerobic glycolysis, based on the detection of less respiratory capacity in accompany with greater lactate production; and/or (2) enhanced ERK1/2-Akt-mTORC-S6 signalling activity in response to TFAM induced mtDNA perturbance. Clinical impacts of TFAM and mtDNA were further defined in carcinogen-induced mouse tongue cancer and clinical human HNC tissues; as the results showed that TFAM and mtDNA expression were significantly dropped in tumour compared with their normal counterparts and negatively correlated with disease progression. Collectively, our data uncovered a tumour-suppressing role of TFAM and mtDNA in determining HNC oncogenicity and potentially paved the way for development of TFAM/mtDNA based scheme for HNC diagnosis.
Highlights
The progression of malignant transformation from non-neoplastic cells to tumourous cells can be achieved only by contribution of a series of cellular events [1]
In the present study, we discovered that lower TFAM and mitochondrial DNA (mtDNA) expression led to decreased mitochondrial activity, which elicited oncogenic pathways to promote tumour
PD98059 showed that PKB/Akt and ERK activities contribute to TFAM-mediated increased cell growth in a dose-dependent manner
Summary
The progression of malignant transformation from non-neoplastic cells to tumourous cells can be achieved only by contribution of a series of cellular events [1]. Our recent study demonstrated that manipulation of a rate-limiting factor of Pyruvate Dehydrogenase complex (PDC), and Pyruvate Dehydrogenase E1 subunit (PDHA1) that controls the metabolic fate of lactate entering into mitochondria, could sufficiently enhance HNC cellular malignancy [26]. This is interesting to further verify the role of mitochondrial genome and generated by applying increasing dose of candidate drugs/treatment for multiple selection cycles onto parental HNC cells (sensitive counterpart).
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