Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer.
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.
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, 28040 Madrid, Spain.
Oscar
O
Aguilera
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, 28040 Madrid, Spain.
María
M
Muñoz-Sagastibelza
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, 28040 Madrid, Spain.
Blanca
B
Torrejón
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, 28040 Madrid, Spain.
Aurea
A
Borrero-Palacios
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, 28040 Madrid, Spain.
Laura
L
Del Puerto-Nevado
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, 28040 Madrid, Spain.
Javier
J
Martínez-Useros
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, 28040 Madrid, Spain.
María
M
Rodriguez-Remirez
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, 28040 Madrid, Spain.
Sandra
S
Zazo
Translational Oncology Division, Oncohealth Institute, Fundacion Jimenez Diaz University Hospital, 28040 Madrid, Spain.|Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, 33011 Oviedo, Spain.
Estela
E
García
Translational Oncology Division, Oncohealth Institute, Fundacion Jimenez Diaz University Hospital, 28040 Madrid, Spain.|Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, 33011 Oviedo, Spain.
Mario
M
Fraga
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, 28040 Madrid, Spain.
Federico
F
Rojo
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, 28040 Madrid, Spain.
Jesús
J
García-Foncillas
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C117307:KRAS protein, human; D017382:Reactive Oxygen Species; D016283:Proto-Oncogene Proteins p21(ras); D001205:Ascorbic Acid; D000068818:Cetuximab
GLUT-1; Warburg; colon cancer; vitamin C