title: Augmented pentose phosphate pathway plays critical roles in colorectal carcinomas.
abstract: Glycolysis and the pentose phosphate pathway (PPP) are preferentially activated in cancer cells. Accumulating evidence indicated the significance of the altered glucose metabolism in cancer, but the implication for oncotherapy remains unclear. Here we report that the synthesis of glycolytic and PPP enzymes is almost ubiquitously augmented in colorectal carcinoma (CRC) specimens. The mammalian target of rapamycin (mTOR) inhibitor INK128 (300 nM) and phytochemical Avemar (1 mg/ml) inhibited the synthesis of PPP enzymes in CRC cell lines. INK128 (150-600 nM) and resveratrol (75-300 μM) inhibited aerobic glycolysis in the cell lines. INK128 (300 nM) and Avemar (1 mg/ml) decreased the NADPH/NADP(+) ratio as well as the GSH/GSSG ratio in the cell lines. Finally, per os administration of INK128 (0.8 mg/kg) or Avemar (1 g/kg) suppressed tumor growth and delayed tumor formation by transplantable CRC specimens derived from patients. Taken together, pharmacological inhibition of the mTOR-PPP axis is a promising therapeutic strategy against CRCs.
authors.affiliation: Second Department of Surgery, Dokkyo Medical University, Mibu, Japan.
authors.forename: Norisuke
authors.initials: N
authors.lastname: Shibuya
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inoue
authors.forename: Genki
authors.initials: G
authors.lastname: Tanaka
authors.forename: Kazumi
authors.initials: K
authors.lastname: Akimoto
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kubota
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001583:Benzoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007564:Japan; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010427:Pentose Phosphate Pathway / Q000187:drug effects*; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D018000:Receptors, Peptide / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D000970:Antineoplastic Agents; D001583:Benzoxazoles; D005947:Glucose; D019803:Glutathione Disulfide; D019344:Lactic Acid; D010936:Plant Extracts; D011743:Pyrimidines; D018000:Receptors, Peptide; D000077185:Resveratrol; D013267:Stilbenes; D058570:TOR Serine-Threonine Kinases; C113915:Avemar; C035560:glutathione receptor; C546842:MTOR protein, human; C572449:sapanisertib; D000225:Adenine