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Mol. Cells 2011; 31(3): 231-238

Published online March 31, 2011

https://doi.org/10.1007/s10059-011-0034-6

© The Korean Society for Molecular and Cellular Biology

Targeting the Autophagy Pathway Using Ectopic Expression of Beclin 1 in Combination with Rapamycin in Drug-Resistant v-Ha-ras-Transformed NIH 3T3 Cells

Ki-Hwan Eum, and Michael Lee*

Division of Life Sciences, College of Natural Sciences, University of Incheon, Incheon 406-772, Korea

Correspondence to : *Correspondence: mikelee@incheon.ac.kr

Received: August 20, 2010; Revised: November 24, 2010; Accepted: December 20, 2010

Abstract

The effectiveness of an apoptosis-targeting therapy may be limited in tumor cells with defects in apoptosis. Recen-tly, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target (mTOR), inhibition of which results in autophagic cell death. In our study using multidrug-resistant v-Ha-ras-transformed NIH3T3 (Ras-NIH 3T3/Mdr) cells, we demon-strated that rapamycin-induced cell death may result from 2 different mechanisms. At high rapamycin concentrations (≥100 nM), cell death may occur via an autophagy-depen-dent pathway, whereas at lower concentrations (≤ 10 nM), cell death may occur after G1-phase cell cycle arrest. This effect was accompanied by upregulation of p21Cip1 and p27Kip1 expression via an autophagy-independent pathway. We also tested whether inhibition of mTOR with low con-centrations of rapamycin and ectopic Beclin-1 expression would further sensitize multidrug resistance (MDR)-posi-tive cancer cells by upregulating autophagy. Rapamycin at low concentrations might be insufficient to initiate auto-phagosome formation in autophagy but Beclin-1 overex-pression triggered additional processes downstream of mTOR during G1 cell cycle arrest by rapamycin. Our find-ings suggest that these combination strategies targeting autophagic cell death may yield significant benefits for cancer patients, because lowering rapamycin concentra-tion for cancer treatment minimizes its side effects in pa-tients undergoing chemotherapy.

Keywords autophagy, Beclin 1, chemotherapy, MDR, Rapamycin

Article

Research Article

Mol. Cells 2011; 31(3): 231-238

Published online March 31, 2011 https://doi.org/10.1007/s10059-011-0034-6

Copyright © The Korean Society for Molecular and Cellular Biology.

Targeting the Autophagy Pathway Using Ectopic Expression of Beclin 1 in Combination with Rapamycin in Drug-Resistant v-Ha-ras-Transformed NIH 3T3 Cells

Ki-Hwan Eum, and Michael Lee*

Division of Life Sciences, College of Natural Sciences, University of Incheon, Incheon 406-772, Korea

Correspondence to:*Correspondence: mikelee@incheon.ac.kr

Received: August 20, 2010; Revised: November 24, 2010; Accepted: December 20, 2010

Abstract

The effectiveness of an apoptosis-targeting therapy may be limited in tumor cells with defects in apoptosis. Recen-tly, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target (mTOR), inhibition of which results in autophagic cell death. In our study using multidrug-resistant v-Ha-ras-transformed NIH3T3 (Ras-NIH 3T3/Mdr) cells, we demon-strated that rapamycin-induced cell death may result from 2 different mechanisms. At high rapamycin concentrations (≥100 nM), cell death may occur via an autophagy-depen-dent pathway, whereas at lower concentrations (≤ 10 nM), cell death may occur after G1-phase cell cycle arrest. This effect was accompanied by upregulation of p21Cip1 and p27Kip1 expression via an autophagy-independent pathway. We also tested whether inhibition of mTOR with low con-centrations of rapamycin and ectopic Beclin-1 expression would further sensitize multidrug resistance (MDR)-posi-tive cancer cells by upregulating autophagy. Rapamycin at low concentrations might be insufficient to initiate auto-phagosome formation in autophagy but Beclin-1 overex-pression triggered additional processes downstream of mTOR during G1 cell cycle arrest by rapamycin. Our find-ings suggest that these combination strategies targeting autophagic cell death may yield significant benefits for cancer patients, because lowering rapamycin concentra-tion for cancer treatment minimizes its side effects in pa-tients undergoing chemotherapy.

Keywords: autophagy, Beclin 1, chemotherapy, MDR, Rapamycin

Mol. Cells
Jan 31, 2023 Vol.46 No.1, pp. 1~67
COVER PICTURE
RNAs form diverse shapes and play multiple functions as central molecules of gene expression. In this special issue on RNA, seven minireviews illustrate how basic concepts and recent RNA biology findings are transformed into new and exciting RNA therapeutics.

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