Selection of cancer cells with repressed mitochondria triggers colon cancer progression

Abstract

The contribution that mitochondrial bioenergetics could have in cancer development is debated. Here, we have generated HCT116-derived colocarcinoma cell lines expressing different levels of the beta catalytic subunit of the mitochondrial H+-adenosine triphosphate synthase to assess the contribution of mitochondrial bioenergetics in colon cancer progression. The generated cells exhibit large ultrastructural, transcriptomic, proteomic and functional differences in their mitochondria and in their in vivo tumor forming capacity. We show that the activity of oxidative phosphorylation defines the rate of glucose utilization by aerobic glycolysis. The aggressive cellular phenotype, which is highly glycolytic, is bound to the deregulated expression of genes involved in metabolic processes, the regulation of the cell cycle, apoptosis, angiogenesis and cell adhesion. Remarkably, the molecular and ultrastructural analysis of the tumors derived from the three HCT116 cell lines under study highlight that tumor promotion inevitably requires the selection of cancer cells with a repressed biogenesis and functional activity of mitochondria, i.e. the highly glycolytic phenotype is selected for tumor development. The tumor forming potential of the cells is a non-genetically acquired condition that provides the cancer cell with a cell-death resistant phenotype. An abrogated mitochondrial respiration contributes to a diminished potential for reactive oxygen species signaling in response to 5-fluorouracil treatment. Treatment of cancer cells with dichloroacetate partially restores the functional differentiation of mitochondria and promotes tumor regression, emphasizing the reversible nature of the metabolic trait of cancer.

Up-regulation of the ATPase Inhibitory Factor 1 (IF1) of the Mitochondrial H+-ATP Synthase in Human Tumors Mediates the Metabolic Shift of Cancer Cells to a Warburg Phenotype

“…Remarkably, oligomycin treatment of IF1-silenced cells restored the original rates of aerobic glycolysis (Fig. 4A), strongly supporting the link between the bioenergetic activity of mitochondria and glucose consumption rates (12,15). Consistently, the determination of the activity of oxidative phosphorylation indicated that IF1-silenced cells had a higher oligomycin sensitive respiratory rate than controls (Fig.…”

“…Glycolysis is known to provide an advantageous phenotype that favors cellular proliferation and invasion (15,37). Moreover, limiting the activity of the H ϩ -ATP synthase also contributes to tumor growth because oxidative phosphorylation is required for the efficient execution of cell death (38 -40).…”

“…During ischemia, the ATP hydrolytic activity of the enzyme is inhibited by the ATPase inhibitory factor 1 (IF1 In oxidative phosphorylation, ATP is synthesized by the mitochondrial ATP synthase, a H ϩ -driven rotatory engine of the inner membrane that utilizes as driving force for ATP synthesis the H ϩ electrochemical gradient generated by the respiratory chain (1-4). The cellular expression level of ␤-F1-ATPase, 2 which is the catalytic subunit of the H ϩ -ATP synthase, is diminished in diverse human pathologies (5), which include cancer (6 -9), affording a relevant marker of disease progression (6, 7, 10 -12) and of the response to chemotherapy (7,(13)(14)(15). Moreover, the down-regulation of ␤-F1-ATPase in lung carcinomas (12) and colon cancer cells (15) also provides a mechanistic explanation to the increased glucose avidity of carcinomas, i.e.…”

“…The cellular expression level of ␤-F1-ATPase, 2 which is the catalytic subunit of the H ϩ -ATP synthase, is diminished in diverse human pathologies (5), which include cancer (6 -9), affording a relevant marker of disease progression (6, 7, 10 -12) and of the response to chemotherapy (7,(13)(14)(15). Moreover, the down-regulation of ␤-F1-ATPase in lung carcinomas (12) and colon cancer cells (15) also provides a mechanistic explanation to the increased glucose avidity of carcinomas, i.e.…”

Oxidative DNA damage drives carcinogenesis in MUTYH-associated-polyposis by specific mutations of mitochondrial and MAPK genes

“…16 In addition to rRNA and tRNA genes, the phylogenetically conserved region of mitochondrial DNA includes sequences encoding for some of the polypeptides which have a role in the control of electron chain transport, such as cytochrome oxidase I and II subunits (MT-CO1/MT-CO2). Mutations affecting these genes have been identified in colorectal cancer cell lines as well as in tumor specimens from colorectal cancer patients.…”