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.
View: Text | PDF
Research Article Oncology

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

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

×

Figure 1

Effects of CQ with and without p53 activation on the regression of Myc/p53ERTAM lymphomas.

Options: View larger image (or click on image) Download as PowerPoint
Effects of CQ with and without p53 activation on the regression of Myc/p...
(A) CQ impairs tumor growth. Cells from a primary Myc/p53ERTAMtumor were harvested and passaged in vivo in 6 syngeneic C57BL/6×129F1 mice. Cells were injected subcutaneously into the flanks of mice. When tumors reached a volume of more than 1,000 mm3, mice were assigned to daily PBS i.p. or 60 mg/kg/d CQ i.p. Results shown are mean ± SD daily tumor volumes and are representative of multiple experiments. *P < 0.05. (B) CQ delays tumor recurrence after p53-induced tumor regression. Myc/p53ERTAM cells were injected subcutaneously into the flanks of 18 C57BL/6×129F1 mice. Once tumors reached a volume of more than 1,500 mm3, mice were assigned to daily treatment (arrow) with 1 mg/d TAM i.p. plus saline (TAM/PBS) or 1 mg/d TAM i.p. plus 60 mg/kg/d CQ i.p. (TAM/CQ). Results shown are daily tumor volumes (mean ± SD) for each group from a representative experiment. *P < 0.05; **P < 0.005.