Abstract
Acquired apoptosis resistance plays an important role in acquired chemoresistance in cancer cells during chemotherapy. Our previous observations demonstrated that acquired tumor necrosis factor-related apoptosis-inducing ligand resistance in lung cancer cells was associated with Akt-mediated stabilization of cellular FLICE-like inhibitory protein (c-FLIP) and Mcl-1. In this report, we determined that these cells also have acquired resistance to apoptosis induced by chemotherapeutics such as cisplatin and doxorubicin (Adriamycin), which was detected in vitro in cell cultures and in vivo in xenografted tumors. We further found that cyclooxygenase-2 (COX-2) is dramatically overexpressed in cells with acquired apoptosis resistance. COX-2 seems to be a crucial mediator in acquired apoptosis resistance because suppressing COX-2 activity with a chemical inhibitor or reducing COX-2 protein expression level with COX-2 small interfering RNA dramatically alleviated resistance to therapeutic-induced apoptosis. Inhibiting Akt markedly suppressed COX-2 expression, suggesting COX-2 is a downstream effector of this cell survival kinase-mediated apoptosis resistance. Furthermore, the expression of Mcl-1 but not c-FLIP was significantly reduced when COX-2 was suppressed, and knockdown of Mcl-1 substantially sensitized the cells to apoptosis. Our results establish a novel pathway that consists of Akt, COX-2, and Mcl-1 for acquired apoptosis resistance, which could be a molecular target for circumventing acquired chemoresistance in lung cancer.
Footnotes
This study is supported in part by the National Institutes of Health National Cancer Institute [Grant R03-CA125796] and the Department of Energy Low Dose Radiation Research Program [Grant DE-SC0001173].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.061226
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ABBREVIATIONS:
- TRAIL
- tumor necrosis factor-related apoptosis-inducing ligand
- Adr
- doxorubicin
- CDDP
- cisplatin
- COX-2
- cyclooxygenase-2
- c-FLIP
- cellular FLICE-like inhibitory protein
- DR
- death receptor
- PC
- parental cell
- TR
- tumor necrosis factor-related apoptosis-inducing ligand-resistant
- TNF
- tumor necrosis factor
- siRNA
- small interfering RNA
- IKK
- IκB kinase complex
- PARP
- poly(ADP-ribose) polymerase
- LDH
- lactate dehydrogenase
- PCR
- polymerase chain reaction
- RT-PCR
- reverse transcription-polymerase chain reaction
- PI3K
- phosphatidylinositol 3-kinase
- GSK3β
- glycogen synthase kinase 3β
- z-VAD
- N-benzyloxycarbonyl-Val-Ala-Asp-
- LY294002
- 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride.
- Received September 21, 2009.
- Accepted November 23, 2009.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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