Oxidative Phosphorylation as a Target to Arrest Malignant Neoplasias

Abstract

Since Warburg proposed in 1956 that cancer cells exhibit increased glycolysis due to mitochondrial damage, numerous researchers have assumed that glycolysis is the predominant ATP supplier for cancer cell energy-dependent processes. However, chemotherapeutic strategies using glycolytic inhibitors have been unsuccessful in arresting tumor proliferation indicating that the Warburg hypothesis may not be applicable to all existing neoplasias. This review analyzes recent information on mitochondrial metabolism in several malignant neoplasias emphasizing that, although tumor cells maintain a high glycolytic rate, the principal ATP production may derive from active oxidative phosphorylation. Thus, anti-mitochondrial drug therapy may be an adequate adjuvant strategy to arrest proliferation of oxidative phosphorylation-dependent neoplasias.

c-Myc Programs Fatty Acid Metabolism and Dictates Acetyl-CoA Abundance and Fate

“…In fact, provided sufficient oxygen, both glycolysis and Oxphos are often concurrently increased in tumor cells (5,6). A particularly instructive example of this occurs with Myc oncoprotein deregulation, which, in addition to stimulating glycolysis, also increases mitochondrial mass, Oxphos, and electron transport chain function (7,8).…”

Association of cancer metabolism-related proteins with oral carcinogenesis – indications for chemoprevention and metabolic sensitizing of oral squamous cell carcinoma?

“…However, very few data is available describing a mitochondrial oxidative metabolism [27] in OSCC. Authors assume that OXPHOS is an important pathway for the generation of ATP [11,22,23] and ROS [18,55-58] during the carcinogenesis of OSCC. The TUNEL assay demonstrated that tumor cells do not undergo apoptosis and therefore, increased ROS generation by OXPHOS does not reach toxic levels.…”

“…This enhanced rate of ATP generation has been postulated to be beneficial for rapidly proliferating cells. However, several studies have suggested that OXPHOS is the major source of cellular ATP in proliferating and non-proliferating [21] cancer cells [11,21-23]. …”

Mitochondrial free fatty acid β-oxidation supports oxidative phosphorylation and proliferation in cancer cells

“…Here, we demonstrated that several substrates are actively oxidized by tumor mitochondria (cf . Tables 2 and 3) to provide Krebs cycle intermediaries such as 2OG (i.e., glutamate, glutamine) and acetyl-CoA (FFAs, propionate, pyruvate) (Rodríguez-Enríquez et al, 2011).…”

“…Proline and propionate oxidations generate glutamate and succinyl CoA, respectively, whereas ketone bodies oxidation forms acetyl-CoA. Although proline oxidase and succinylCoA acetoacetyl transferase (SCAAT) activities are 4 and 40-times higher in some tumor mitochondria vs. normal ones (reviewed in Rodríguez-Enríquez et al, 2011), it was shown that both enzyme activities were low in AS-30D cells. In fact, there are no studies analyzing AS-30D mitochondrial POX content.…”