title: Reciprocal regulation of autophagy and dNTP pools in human cancer cells.
abstract: Ribonucleotide reductase (RNR) plays a critical role in catalyzing the biosynthesis and maintaining the intracellular concentration of 4 deoxyribonucleoside triphosphates (dNTPs). Unbalanced or deficient dNTP pools cause serious genotoxic consequences. Autophagy is the process by which cytoplasmic constituents are degraded in lysosomes to maintain cellular homeostasis and bioenergetics. However, the role of autophagy in regulating dNTP pools is not well understood. Herein, we reported that starvation- or rapamycin-induced autophagy was accompanied by a decrease in RNR activity and dNTP pools in human cancer cells. Furthermore, downregulation of the small subunit of RNR (RRM2) by siRNA or treatment with the RNR inhibitor hydroxyurea substantially induced autophagy. Conversely, cancer cells with abundant endogenous intracellular dNTPs or treated with dNTP precursors were less responsive to autophagy induction by rapamycin, suggesting that autophagy and dNTP pool levels are regulated through a negative feedback loop. Lastly, treatment with si-RRM2 caused an increase in MAP1LC3B, ATG5, BECN1, and ATG12 transcript abundance in xenografted Tu212 tumors in vivo. Together, our results revealed a previously unrecognized reciprocal regulation between dNTP pools and autophagy in cancer cells.
authors.affiliation: Department of Food Science and Nutrition; Zhejiang Key Laboratory for Agro-Food Processing; Zhejiang University; Hangzhou, China; Department of Molecular Pharmacology; Beckman Research Institute; City of Hope National Medical Center; Duarte, CA USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Molecular Pharmacology; Beckman Research Institute; City of Hope National Medical Center; Duarte, CA USA; School of Veterinary Medicine; Huazhong Agricultural University; Wuhan, China.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Molecular Pharmacology; Beckman Research Institute; City of Hope National Medical Center; Duarte, CA USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Molecular Pharmacology; Beckman Research Institute; City of Hope National Medical Center; Duarte, CA USA.
authors.forename: Bingsen
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Molecular Pharmacology; Beckman Research Institute; City of Hope National Medical Center; Duarte, CA USA.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Kuo
authors.affiliation: Department of Molecular Pharmacology; Beckman Research Institute; City of Hope National Medical Center; Duarte, CA USA.
authors.forename: Shuya
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Molecular Pharmacology; Beckman Research Institute; City of Hope National Medical Center; Duarte, CA USA.
authors.forename: Linling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Molecular Pharmacology; Beckman Research Institute; City of Hope National Medical Center; Duarte, CA USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Tang
authors.affiliation: Department of Molecular Pharmacology; Beckman Research Institute; City of Hope National Medical Center; Duarte, CA USA.
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Chen
authors.affiliation: Department of Molecular Pharmacology; Beckman Research Institute; City of Hope National Medical Center; Duarte, CA USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Molecular Pharmacology; Beckman Research Institute; City of Hope National Medical Center; Duarte, CA USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
authors.affiliation: Department of Molecular Pharmacology; Beckman Research Institute; City of Hope National Medical Center; Duarte, CA USA; Taipei Medical University; Taipei, Taiwan.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009711:Nucleotides / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012262:Ribonucleoside Diphosphate Reductase / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D009711:Nucleotides; D034741:RNA, Small Interfering; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D020123:Sirolimus; D006918:Hydroxyurea
keywords: RRM2; autophagy; dNTP pools; rapamycin; ribonucleotide reductase