Celecoxib-induced Apoptosis is Enhanced by ABT-737 and by Inhibition of Autophagy in Human Colorectal Cancer Cells

Overview

Journal Autophagy

Specialty Cell Biology

Date 2010 Jan 28

PMID 20104024

Citations 73

Authors

Shengbing Huang

Frank A Sinicrope

Affiliations

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Abstract

Apoptosis and autophagy have been shown to be negatively regulated by prosurvival Bcl-2 proteins. We determined whether the anticancer agent celecoxib, alone or combined with a small molecule Bcl-2/Bcl-x(L) antagonist (ABT-737), can induce autophagy in colon cancer cells. Furthermore, we determined whether inhibition of autophagy can drive colon cancer cells into apoptosis. Celecoxib was shown to induce apoptosis that was attenuated by ectopic Bcl-2 or Bax knockout. ABT-737 synergistically enhanced celecoxib-induced cytotoxicity that was primarily due to apoptosis as shown by caspase cleavage and Annexin V labeling that was attenuated by a pan caspase inhibitor (z-VAD-fmk). Celecoxib triggered conversion of the autophagosome-associated protein light chain 3 (LC3) from a cytosolic (LC3I) to a membrane-bound (LC3II) form, as shown by immunoblotting and a punctate fluorescence pattern of an ectopic GFP-LC3 protein. Celecoxib-induced conversion of LC3 was due to autophagy induction, as supported using the lysosome inhibitor, bafilomycin A1, which produced an accumulation of LC3II. ABT-737 enhanced celecoxib-induced LC3 conversion and p62/SQSTM1 degradation. Inhibition of autophagy was then studied in an effort to drive cells into apoptosis. 3-methyladenine (3-MA) blocked LC3 conversion, and 3-MA and wortmannin significantly enhanced apoptotic signaling in cells treated with celecoxib plus ABT-737. Furthermore, knockdown of Atg8/LC3B or Vps34 using siRNA attenuated p62 degradation and enhanced apoptotic signaling; Vps34 siRNA potentiated annexin V(+), PI(-) labeled cells induced by celecoxib + ABT-737. In conclusion, celecoxib induces apoptosis and autophagy that can both be potentiated by ABT-737. Inhibition of autophagy was shown to enhance apoptosis, suggesting a novel therapeutic strategy against colon cancer.

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References

Levine B, Kroemer G . Autophagy in the pathogenesis of disease. Cell. 2008; 132(1):27-42. PMC: 2696814. DOI: 10.1016/j.cell.2007.12.018. View

Tsutsumi S, Gotoh T, Tomisato W, Mima S, Hoshino T, Hwang H . Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis. Cell Death Differ. 2004; 11(9):1009-16. DOI: 10.1038/sj.cdd.4401436. View

Johnsen J, Lindskog M, Ponthan F, Pettersen I, Elfman L, Orrego A . Cyclooxygenase-2 is expressed in neuroblastoma, and nonsteroidal anti-inflammatory drugs induce apoptosis and inhibit tumor growth in vivo. Cancer Res. 2004; 64(20):7210-5. DOI: 10.1158/0008-5472.CAN-04-1795. View

Herman-Antosiewicz A, Johnson D, Singh S . Sulforaphane causes autophagy to inhibit release of cytochrome C and apoptosis in human prostate cancer cells. Cancer Res. 2006; 66(11):5828-35. DOI: 10.1158/0008-5472.CAN-06-0139. View

Hida T, Kozaki K, Muramatsu H, Masuda A, Shimizu S, Mitsudomi T . Cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines. Clin Cancer Res. 2000; 6(5):2006-11. View

Grosch S, Tegeder I, Niederberger E, Brautigam L, Geisslinger G . COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. FASEB J. 2001; 15(14):2742-4. DOI: 10.1096/fj.01-0299fje. View

Pankiv S, Clausen T, Lamark T, Brech A, Bruun J, Outzen H . p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007; 282(33):24131-45. DOI: 10.1074/jbc.M702824200. View

Abedin M, Wang D, McDonnell M, Lehmann U, Kelekar A . Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ. 2006; 14(3):500-10. DOI: 10.1038/sj.cdd.4402039. View

Tahir S, Yang X, Anderson M, Morgan-Lappe S, Sarthy A, Chen J . Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res. 2007; 67(3):1176-83. DOI: 10.1158/0008-5472.CAN-06-2203. View

10.

Pyrko P, Kardosh A, Liu Y, Soriano N, Xiong W, Chow R . Calcium-activated endoplasmic reticulum stress as a major component of tumor cell death induced by 2,5-dimethyl-celecoxib, a non-coxib analogue of celecoxib. Mol Cancer Ther. 2007; 6(4):1262-75. DOI: 10.1158/1535-7163.MCT-06-0629. View

11.

Huang S, Okumura K, Sinicrope F . BH3 mimetic obatoclax enhances TRAIL-mediated apoptosis in human pancreatic cancer cells. Clin Cancer Res. 2009; 15(1):150-9. PMC: 2948485. DOI: 10.1158/1078-0432.CCR-08-1575. View

12.

Oltersdorf T, Elmore S, Shoemaker A, Armstrong R, Augeri D, Belli B . An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435(7042):677-81. DOI: 10.1038/nature03579. View

13.

van Delft M, Wei A, Mason K, Vandenberg C, Chen L, Czabotar P . The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 2006; 10(5):389-99. PMC: 2953559. DOI: 10.1016/j.ccr.2006.08.027. View

14.

Kondo Y, Kanzawa T, Sawaya R, Kondo S . The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005; 5(9):726-34. DOI: 10.1038/nrc1692. View

15.

Liu X, Yue P, Zhou Z, Khuri F, Sun S . Death receptor regulation and celecoxib-induced apoptosis in human lung cancer cells. J Natl Cancer Inst. 2004; 96(23):1769-80. DOI: 10.1093/jnci/djh322. View

16.

Levine B, Kroemer G . Autophagy in aging, disease and death: the true identity of a cell death impostor. Cell Death Differ. 2008; 16(1):1-2. PMC: 2717606. DOI: 10.1038/cdd.2008.139. View

17.

Huang S, Sinicrope F . BH3 mimetic ABT-737 potentiates TRAIL-mediated apoptotic signaling by unsequestering Bim and Bak in human pancreatic cancer cells. Cancer Res. 2008; 68(8):2944-51. PMC: 2948486. DOI: 10.1158/0008-5472.CAN-07-2508. View

18.

Okumura K, Huang S, Sinicrope F . Induction of Noxa sensitizes human colorectal cancer cells expressing Mcl-1 to the small-molecule Bcl-2/Bcl-xL inhibitor, ABT-737. Clin Cancer Res. 2008; 14(24):8132-42. PMC: 2948478. DOI: 10.1158/1078-0432.CCR-08-1665. View

19.

Heath-Engel H, Chang N, Shore G . The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family. Oncogene. 2008; 27(50):6419-33. DOI: 10.1038/onc.2008.309. View

20.

Sato K, Tsuchihara K, Fujii S, Sugiyama M, Goya T, Atomi Y . Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res. 2007; 67(20):9677-84. DOI: 10.1158/0008-5472.CAN-07-1462. View