Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer
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Oscar Aguilera1, María Muñoz-Sagastibelza1, Blanca Torrejón1, Aurea Borrero-Palacios1, Laura del Puerto-Nevado1, Javier Martínez-Useros1, María Rodriguez-Remirez1, Sandra Zazo1, Estela García2,3, Mario Fraga2,3, Federico Rojo1, Jesús García-Foncillas1
1Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, 28040 Madrid, Spain
2Translational Oncology Division, Oncohealth Institute, Fundacion Jimenez Diaz University Hospital, 28040 Madrid, Spain
3Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, 33011 Oviedo, Spain
Federico Rojo, email: [email protected]
Jesús García-Foncillas, email: [email protected]
Keywords: colon cancer, Warburg, vitamin C, GLUT-1
Received: March 30, 2016 Accepted: May 29, 2016 Published: June 15, 2016
KRAS mutation is often present in many hard-to-treat tumors such as colon and pancreatic cancer and it is tightly linked to serious alterations in the normal cell metabolism and clinical resistance to chemotherapy.
In 1931, the winner of the Nobel Prize in Medicine, Otto Warburg, stated that cancer was primarily caused by altered metabolism interfering with energy processing in the normal cell. Increased cell glycolytic rates even in the presence of oxygen is fully recognized as a hallmark in cancer and known as the Warburg effect.
In the late 1970's, Linus Pauling and Ewan Cameron reported that vitamin C may have positive effects in cancer treatment, although deep mechanistic knowledge about this activity is still scarce.
We describe a novel antitumoral mechanism of vitamin C in KRAS mutant colorectal cancer that involves the Warburg metabolic disruption through downregulation of key metabolic checkpoints in KRAS mutant cancer cells and tumors without killing human immortalized colonocytes.
Vitamin C induces RAS detachment from the cell membrane inhibiting ERK 1/2 and PKM2 phosphorylation. As a consequence of this activity, strong downregulation of the glucose transporter (GLUT-1) and pyruvate kinase M2 (PKM2)-PTB dependent protein expression are observed causing a major blockage of the Warburg effect and therefore energetic stress.
We propose a combination of conventional chemotherapy with metabolic strategies, including vitamin C and/or other molecules targeting pivotal key players involved in the Warburg effect which may constitute a new horizon in anti-cancer therapies.
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