Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer

// Oscar Aguilera 1 , Maria Munoz-Sagastibelza 1 , Blanca Torrejon 1 , Aurea Borrero-Palacios 1 , Laura del Puerto-Nevado 1 , Javier Martinez-Useros 1 , Maria Rodriguez-Remirez 1 , Sandra Zazo 1 , Estela Garcia 2, 3 , Mario Fraga 2, 3 , Federico Rojo 1 , Jesus Garcia-Foncillas 1 1 Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, 28040 Madrid, Spain 2 Translational Oncology Division, Oncohealth Institute, Fundacion Jimenez Diaz University Hospital, 28040 Madrid, Spain 3 Cancer Epigenetics Laboratory, Instituto Universitario de Oncologia del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, 33011 Oviedo, Spain Correspondence to: Federico Rojo, email: frojo@fjd.es Jesus Garcia-Foncillas, email: jgfoncillas@idcsalud.es Keywords: colon cancer, Warburg, vitamin C, GLUT-1 Received: March 30, 2016      Accepted: May 29, 2016      Published: June 15, 2016 ABSTRACT 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.