title: Cancer usurps skeletal muscle as an energy repository.
abstract: Cancer cells produce energy through aerobic glycolysis, but contributions of host tissues to cancer energy metabolism are unclear. In this study, we aimed to elucidate the cancer-host energy production relationship, in particular, between cancer energy production and host muscle. During the development and progression of colorectal cancer, expression of the secreted autophagy-inducing stress protein HMGB1 increased in the muscle of tumor-bearing animals. This effect was associated with decreased expression of pyruvate kinase PKM1 and pyruvate kinase activity in muscle via the HMGB1 receptor for advanced glycation endproducts (RAGE). However, muscle mitochondrial energy production was maintained. In contrast, HMGB1 addition to colorectal cancer cells increased lactate fermentation. In the muscle, HMGB1 addition induced autophagy by decreasing levels of active mTOR and increasing autophagy-associated proteins, plasma glutamate, and (13)C-glutamine incorporation into acetyl-CoA. In a mouse model of colon carcinogenesis, a temporal increase in HMGB1 occurred in serum and colonic mucosa with an increase in autophagy associated with altered plasma free amino acid levels, increased glutamine, and decreased PKM1 levels. These differences were abolished by administration of an HMGB1 neutralizing antibody. Similar results were obtained in a mouse xenograft model of human colorectal cancer. Taken together, our findings suggest that HMGB1 released during tumorigenesis recruits muscle to supply glutamine to cancer cells as an energy source.
authors.affiliation: Authors' Affiliations: Department of Molecular Pathology, Nara Medical University, Shijo-cho, Kashihara; Institute for Innovation Ajinomoto Co., Inc., Suzuki-cho, Kawasaki; and Department of Gastrointestinal Surgery, Fukuoka University School of Medicine, Nanakuma, Minami-ku, Fukuoka, Japan.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Junya
authors.initials: J
authors.lastname: Yoneda
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohmori
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Shimbo
authors.forename: Sachise
authors.initials: S
authors.lastname: Eto
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyano
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Tomonori
authors.initials: T
authors.lastname: Sasahira
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Chihara
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kuniyasu
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000502:physiology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005973:Glutamine / Q000378:metabolism; D024243:HMGB1 Protein / Q000097:blood / Q000494:pharmacology; D019073:HT29 Cells; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D011994:Recombinant Proteins; D005973:Glutamine