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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
May 31, 2022 Vol.45 No.5, pp. 273~352
COVER PICTURE
Fe2+ ion depletion-induced expression of BΔGFP at the early stage of leaf development (Choi et al., pp. 294-305).

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