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Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma
Ravi K. Amaravadi, … , Andrei Thomas-Tikhonenko, Craig B. Thompson
Ravi K. Amaravadi, … , Andrei Thomas-Tikhonenko, Craig B. Thompson
Published February 1, 2007
Citation Information: J Clin Invest. 2007;117(2):326-336. https://doi.org/10.1172/JCI28833.
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Research Article Oncology

Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma

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Abstract

Autophagy is a lysosome-dependent degradative pathway frequently activated in tumor cells treated with chemotherapy or radiation. Whether autophagy observed in treated cancer cells represents a mechanism that allows tumor cells to survive therapy or a mechanism for initiating a nonapoptotic form of programmed cell death remains controversial. To address this issue, the role of autophagy in a Myc-induced model of lymphoma generated from cells derived from p53ERTAM/p53ERTAM mice (with ER denoting estrogen receptor) was examined. Such tumors are resistant to apoptosis due to a lack of nuclear p53. Systemic administration of tamoxifen led to p53 activation and tumor regression followed by tumor recurrence. Activation of p53 was associated with the rapid appearance of apoptotic cells and the induction of autophagy in surviving cells. Inhibition of autophagy with either chloroquine or ATG5 short hairpin RNA (shRNA) enhanced the ability of either p53 activation or alkylating drug therapy to induce tumor cell death. These studies provide evidence that autophagy serves as a survival pathway in tumor cells treated with apoptosis activators and a rationale for the use of autophagy inhibitors such as chloroquine in combination with therapies designed to induce apoptosis in human cancers.

Authors

Ravi K. Amaravadi, Duonan Yu, Julian J. Lum, Thi Bui, Maria A. Christophorou, Gerard I. Evan, Andrei Thomas-Tikhonenko, Craig B. Thompson

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Figure 4

Effects of p53 activation with and without CQ on LC3 relocalization.

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Effects of p53 activation with and without CQ on LC3 relocalization.
(A–...
(A–C) GFP-LC3 fluorescence. Green, GFP-LC3; blue, DAPI. (A) A bulk population of primary Myc/p53ERTAM lymphoma cells with stable expression of the GFP-LC3 fusion protein was treated with and without 250 nM hTAM and with and without 5 μM CQ. Cell culture medium was changed daily. Cells were fixed and imaged using fluorescence microscopy at 24 and 48 hours. Representative images of cells at 48 hours are presented. (B) Quantification of the percentage of cells with more than 4 GFP-LC3 puncta per cell (punctate) compared with those with less than 4 GFP-LC3 puncta per cell (diffuse) treated with increasing doses of CQ with and without hTAM at 24 hours. (C) CQ modulates autophagy in a p53-independent manner. p53+/+ and p53–/– MEFs expressing GFP-LC3 were treated with CQ. Cells were fixed and imaged at 24 hours.

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