title: 5'-AMP-activated protein kinase (AMPK) supports the growth of aggressive experimental human breast cancer tumors.
abstract: Rapid tumor growth can establish metabolically stressed microenvironments that activate 5'-AMP-activated protein kinase (AMPK), a ubiquitous regulator of ATP homeostasis. Previously, we investigated the importance of AMPK for the growth of experimental tumors prepared from HRAS-transformed mouse embryo fibroblasts and for primary brain tumor development in a rat model of neurocarcinogenesis. Here, we used triple-negative human breast cancer cells in which AMPK activity had been knocked down to investigate the contribution of AMPK to experimental tumor growth and core glucose metabolism. We found that AMPK supports the growth of fast-growing orthotopic tumors prepared from MDA-MB-231 and DU4475 breast cancer cells but had no effect on the proliferation or survival of these cells in culture. We used in vitro and in vivo metabolic profiling with [(13)C]glucose tracers to investigate the contribution of AMPK to core glucose metabolism in MDA-MB-231 cells, which have a Warburg metabolic phenotype; these experiments indicated that AMPK supports tumor glucose metabolism in part through positive regulation of glycolysis and the nonoxidative pentose phosphate cycle. We also found that AMPK activity in the MDA-MB-231 tumors could systemically perturb glucose homeostasis in sensitive normal tissues (liver and pancreas). Overall, our findings suggest that the contribution of AMPK to the growth of aggressive experimental tumors has a critical microenvironmental component that involves specific regulation of core glucose metabolism.
authors.affiliation: Biosciences Division, SRI International, Menlo Park, California 94025,. Electronic address: keith.laderoute@sri.com.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Laderoute
authors.affiliation: Biosciences Division, SRI International, Menlo Park, California 94025.
authors.forename: Joy M
authors.initials: JM
authors.lastname: Calaoagan
authors.affiliation: Biosciences Division, SRI International, Menlo Park, California 94025.
authors.forename: Wan-Ru
authors.initials: WR
authors.lastname: Chao
authors.affiliation: Biosciences Division, SRI International, Menlo Park, California 94025.
authors.forename: Dominc
authors.initials: D
authors.lastname: Dinh
authors.affiliation: Department of Radiation Oncology, The James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Denko
authors.affiliation: Biosciences Division, SRI International, Menlo Park, California 94025.
authors.forename: Sarah
authors.initials: S
authors.lastname: Duellman
authors.affiliation: Department of Biology, Langara College, Vancouver, British Columbia V5W 2Z6, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kalra
authors.affiliation: Biosciences Division, SRI International, Menlo Park, California 94025.
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, The James Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Papandreou
authors.affiliation: Biosciences Division, SRI International, Menlo Park, California 94025.
authors.forename: Lidia
authors.initials: L
authors.lastname: Sambucetti
authors.affiliation: Department of Pediatrics, UCLA School of Medicine, Los Angeles, California 90509,; Los Angeles Biomedical Research Institute at the Harbor-UCLA Medical Center, Torrance, California 90502, and; SIDMAP, LLC, Los Angeles, California 90064.
authors.forename: Laszlo G
authors.initials: LG
authors.lastname: Boros
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010427:Pentose Phosphate Pathway / Q000235:genetics; D051381:Rats
chemical_list: D009363:Neoplasm Proteins; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMP-activated Kinase (AMPK); Glucose Metabolism; Metabolic Profiling; Triple Negative; Tumor Metabolism; Tumor Microenvironment; Warburg Effect