Reciprocal regulation of autophagy and dNTP pools in human cancer cells

Wei Chen, Lisheng Zhang, Keqiang Zhang, Bingsen Zhou, Mei Ling Kuo, Shuya Hu, Linling Chen, Michelle Tang, Yun Ru Chen, Lixin Yang, David K. Ann, Yun Yen

研究成果: 雜誌貢獻文章

21 引文 (Scopus)

摘要

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.

原文英語
頁(從 - 到)1272-1284
頁數13
期刊Autophagy
10
發行號7
DOIs
出版狀態已發佈 - 一月 1 2014

指紋

Deoxyribonucleosides
Autophagy
Ribonucleotide Reductases
Neoplasms
Sirolimus
Hydroxyurea
triphosphoric acid
Starvation
Lysosomes
Energy Metabolism
Small Interfering RNA
Homeostasis
Down-Regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

引用此文

Chen, W., Zhang, L., Zhang, K., Zhou, B., Kuo, M. L., Hu, S., ... Yen, Y. (2014). Reciprocal regulation of autophagy and dNTP pools in human cancer cells. Autophagy, 10(7), 1272-1284. https://doi.org/10.4161/auto.28954

Reciprocal regulation of autophagy and dNTP pools in human cancer cells. / Chen, Wei; Zhang, Lisheng; Zhang, Keqiang; Zhou, Bingsen; Kuo, Mei Ling; Hu, Shuya; Chen, Linling; Tang, Michelle; Chen, Yun Ru; Yang, Lixin; Ann, David K.; Yen, Yun.

於: Autophagy, 卷 10, 編號 7, 01.01.2014, p. 1272-1284.

研究成果: 雜誌貢獻文章

Chen, W, Zhang, L, Zhang, K, Zhou, B, Kuo, ML, Hu, S, Chen, L, Tang, M, Chen, YR, Yang, L, Ann, DK & Yen, Y 2014, 'Reciprocal regulation of autophagy and dNTP pools in human cancer cells', Autophagy, 卷 10, 編號 7, 頁 1272-1284. https://doi.org/10.4161/auto.28954
Chen W, Zhang L, Zhang K, Zhou B, Kuo ML, Hu S 等. Reciprocal regulation of autophagy and dNTP pools in human cancer cells. Autophagy. 2014 1月 1;10(7):1272-1284. https://doi.org/10.4161/auto.28954
Chen, Wei ; Zhang, Lisheng ; Zhang, Keqiang ; Zhou, Bingsen ; Kuo, Mei Ling ; Hu, Shuya ; Chen, Linling ; Tang, Michelle ; Chen, Yun Ru ; Yang, Lixin ; Ann, David K. ; Yen, Yun. / Reciprocal regulation of autophagy and dNTP pools in human cancer cells. 於: Autophagy. 2014 ; 卷 10, 編號 7. 頁 1272-1284.
@article{467e18bea06f4f8cb9000c564f185407,
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.",
keywords = "Autophagy, dNTP pools, Rapamycin, Ribonucleotide reductase, RRM2",
author = "Wei Chen and Lisheng Zhang and Keqiang Zhang and Bingsen Zhou and Kuo, {Mei Ling} and Shuya Hu and Linling Chen and Michelle Tang and Chen, {Yun Ru} and Lixin Yang and Ann, {David K.} and Yun Yen",
year = "2014",
month = "1",
day = "1",
doi = "10.4161/auto.28954",
language = "English",
volume = "10",
pages = "1272--1284",
journal = "Autophagy",
issn = "1554-8627",
publisher = "Landes Bioscience",
number = "7",

}

TY - JOUR

T1 - Reciprocal regulation of autophagy and dNTP pools in human cancer cells

AU - Chen, Wei

AU - Zhang, Lisheng

AU - Zhang, Keqiang

AU - Zhou, Bingsen

AU - Kuo, Mei Ling

AU - Hu, Shuya

AU - Chen, Linling

AU - Tang, Michelle

AU - Chen, Yun Ru

AU - Yang, Lixin

AU - Ann, David K.

AU - Yen, Yun

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - Autophagy

KW - dNTP pools

KW - Rapamycin

KW - Ribonucleotide reductase

KW - RRM2

UR - http://www.scopus.com/inward/record.url?scp=84903825191&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903825191&partnerID=8YFLogxK

U2 - 10.4161/auto.28954

DO - 10.4161/auto.28954

M3 - Article

C2 - 24905824

AN - SCOPUS:84903825191

VL - 10

SP - 1272

EP - 1284

JO - Autophagy

JF - Autophagy

SN - 1554-8627

IS - 7

ER -