title: Mitochondrial free fatty acid β-oxidation supports oxidative phosphorylation and proliferation in cancer cells.
abstract: Oxidative phosphorylation (OxPhos) is functional and sustains tumor proliferation in several cancer cell types. To establish whether mitochondrial β-oxidation of free fatty acids (FFAs) contributes to cancer OxPhos functioning, its protein contents and enzyme activities, as well as respiratory rates and electrical membrane potential (ΔΨm) driven by FFA oxidation were assessed in rat AS-30D hepatoma and liver (RLM) mitochondria. Higher protein contents (1.4-3 times) of β-oxidation (CPT1, SCAD) as well as proteins and enzyme activities (1.7-13-times) of Krebs cycle (KC: ICD, 2OGDH, PDH, ME, GA), and respiratory chain (RC: COX) were determined in hepatoma mitochondria vs. RLM. Although increased cholesterol content (9-times vs. RLM) was determined in the hepatoma mitochondrial membranes, FFAs and other NAD-linked substrates were oxidized faster (1.6-6.6 times) by hepatoma mitochondria than RLM, maintaining similar ΔΨm values. The contents of β-oxidation, KC and RC enzymes were also assessed in cells. The mitochondrial enzyme levels in human cervix cancer HeLa and AS-30D cells were higher than those observed in rat hepatocytes whereas in human breast cancer biopsies, CPT1 and SCAD contents were lower than in human breast normal tissue. The presence of CPT1 and SCAD in AS-30D mitochondria and HeLa cells correlated with an active FFA utilization in HeLa cells. Furthermore, the β-oxidation inhibitor perhexiline blocked FFA utilization, OxPhos and proliferation in HeLa and other cancer cells. In conclusion, functional mitochondria supported by FFA β-oxidation are essential for the accelerated cancer cell proliferation and hence anti-β-oxidation therapeutics appears as an alternative promising approach to deter malignant tumor growth.
authors.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología, Juan Badiano No. 1, Col. Sección 16, Tlalpan, México D.F. 14080, Mexico; Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerología, Ciudad de Mexico, D.F., Mexico. Electronic address: saren960104@hotmail.com.
authors.forename: Sara
authors.initials: S
authors.lastname: Rodríguez-Enríquez
authors.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología, Juan Badiano No. 1, Col. Sección 16, Tlalpan, México D.F. 14080, Mexico.
authors.forename: Luz
authors.initials: L
authors.lastname: Hernández-Esquivel
authors.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología, Juan Badiano No. 1, Col. Sección 16, Tlalpan, México D.F. 14080, Mexico.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Marín-Hernández
authors.affiliation: Departamento de Medicina Cardiovascular, Instituto Nacional de Cardiología, Ciudad de México, D.F., Mexico.
authors.forename: Mohammed
authors.initials: M
authors.lastname: El Hafidi
authors.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología, Juan Badiano No. 1, Col. Sección 16, Tlalpan, México D.F. 14080, Mexico.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Gallardo-Pérez
authors.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología, Juan Badiano No. 1, Col. Sección 16, Tlalpan, México D.F. 14080, Mexico.
authors.forename: Ileana
authors.initials: I
authors.lastname: Hernández-Reséndiz
authors.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología, Juan Badiano No. 1, Col. Sección 16, Tlalpan, México D.F. 14080, Mexico.
authors.forename: José S
authors.initials: JS
authors.lastname: Rodríguez-Zavala
authors.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología, Juan Badiano No. 1, Col. Sección 16, Tlalpan, México D.F. 14080, Mexico.
authors.forename: Silvia C
authors.initials: SC
authors.lastname: Pacheco-Velázquez
authors.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología, Juan Badiano No. 1, Col. Sección 16, Tlalpan, México D.F. 14080, Mexico.
authors.forename: Rafael
authors.initials: R
authors.lastname: Moreno-Sánchez
mesh_terms: D016475:3T3 Cells; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D061986:MCF-7 Cells; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010085:Oxidative Phosphorylation; D051381:Rats; D017208:Rats, Wistar
chemical_list: D005227:Fatty Acids
keywords: Anti-mitochondrial therapy; Cancer cells; Perhexeline; Tumor mitochondria; β-Oxidation