title: Metabolic Alterations Caused by KRAS Mutations in Colorectal Cancer Contribute to Cell Adaptation to Glutamine Depletion by Upregulation of Asparagine Synthetase.
abstract: A number of clinical trials have shown that KRAS mutations of colorectal cancer (CRC) can predict a lack of responses to anti-epidermal growth factor receptor-based therapy. Recently, there have been several studies to elucidate metabolism reprogramming in cancer. However, it remains to be investigated how mutated KRAS can coordinate the metabolic shift to sustain CRC tumor growth. In this study, we found that KRAS mutation in CRC caused alteration in amino acid metabolism. KRAS mutation causes a marked decrease in aspartate level and an increase in asparagine level in CRC. Using several human CRC cell lines and clinical specimens of primary CRC, we demonstrated that the expression of asparagine synthetase (ASNS), an enzyme that synthesizes asparagine from aspartate, was upregulated by mutated KRAS and that ASNS expression was induced by KRAS-activated signaling pathway, in particular PI3K-AKT-mTOR pathway. Importantly, we demonstrated that KRAS-mutant CRC cells could become adaptive to glutamine depletion through asparagine biosynthesis by ASNS and that asparagine addition could rescue the inhibited growth and viability of cells grown under the glutamine-free condition in vitro. Notably, a pronounced growth suppression of KRAS-mutant CRC was observed upon ASNS knockdown in vivo. Furthermore, combination of L-asparaginase plus rapamycin markedly suppressed the growth of KRAS-mutant CRC xenografts in vivo, whereas either L-asparaginase or rapamycin alone was not effective. These results indicate ASNS might be a novel therapeutic target against CRCs with mutated KRAS.
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Toda
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. Electronic address: kkawada@kuhp.kyoto-u.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawada
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Iwamoto
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Inamoto
authors.affiliation: Institute for Advanced Study, Kyushu University, Fukuoka, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.affiliation: Departments of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; Gastroenterological Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Hasegawa
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Sakai
mesh_terms: D000220:Adaptation, Biological; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001217:Aspartate-Ammonia Ligase / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005973:Glutamine / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D047368:Tumor Burden; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000596:Amino Acids; D001217:Aspartate-Ammonia Ligase; D005973:Glutamine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins