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Bax plays a pivotal role in thapsigargin-induced apoptosis of human colon cancer HCT116 cells by controlling Smac/Diablo and Omi/HtrA2 release from mitochondria.
Cancer Res. 2003 Apr 01; 63(7):1483-9.CR

Abstract

Bax is a crucial mediator of the mitochondrial pathway for apoptosis, and loss of this proapoptotic Bcl-2 family protein contributes to drug resistance in human cancers. We report here that the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin (THG) induces apoptosis of human colon cancer HCT116 cells through a Bax-dependent signaling pathway controlling the cytosolic release of mitochondrial apoptogenic molecules. Treating HCT116 cells with THG results in caspase-8 activation; Bid cleavage; Bax conformational change and mitochondrial translocation; the release of cytochrome c, Smac/Diablo, and Omi/HtrA2 into the cytosol; caspase-3 activation; and apoptosis. In contrast, knockout of Bax completely abrogates the full processing/activation of caspase-3 but has no effect on the processing of caspase-8 and the initial cleavage of caspase-3 to p24 fragment after THG treatment. The caspase-8-specific inhibitor z-IETD-fmk, as well as pan-caspase inhibitor z-VAD-fmk, but not the calpain inhibitor E-64d, prevents Bid cleavage, Bax conformational change, and subsequent caspase-3 processing and apoptosis. Caspase-8 processing is dependent on de novo protein synthesis; DR5 expression is strongly up-regulated by THG treatment. Moreover, the absence of Bax blocks THG-induced Omi and Smac release from mitochondria, and expression of cytosolic Omi (GFP-IETD-Omi) or Smac (GFP-IETD-Smac) restores the sensitivity of Bax-knockout HCT116 cells to apoptosis in response to THG treatment. Taken together, our results indicate that Bax-dependent Smac and Omi release plays an essential role in caspase-3 activation and apoptosis induced by THG in human colon cancer HCT116 cells.

Authors+Show Affiliations

Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, Florida 33612, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12670894

Citation

Yamaguchi, Hirohito, et al. "Bax Plays a Pivotal Role in Thapsigargin-induced Apoptosis of Human Colon Cancer HCT116 Cells By Controlling Smac/Diablo and Omi/HtrA2 Release From Mitochondria." Cancer Research, vol. 63, no. 7, 2003, pp. 1483-9.
Yamaguchi H, Bhalla K, Wang HG. Bax plays a pivotal role in thapsigargin-induced apoptosis of human colon cancer HCT116 cells by controlling Smac/Diablo and Omi/HtrA2 release from mitochondria. Cancer Res. 2003;63(7):1483-9.
Yamaguchi, H., Bhalla, K., & Wang, H. G. (2003). Bax plays a pivotal role in thapsigargin-induced apoptosis of human colon cancer HCT116 cells by controlling Smac/Diablo and Omi/HtrA2 release from mitochondria. Cancer Research, 63(7), 1483-9.
Yamaguchi H, Bhalla K, Wang HG. Bax Plays a Pivotal Role in Thapsigargin-induced Apoptosis of Human Colon Cancer HCT116 Cells By Controlling Smac/Diablo and Omi/HtrA2 Release From Mitochondria. Cancer Res. 2003 Apr 1;63(7):1483-9. PubMed PMID: 12670894.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bax plays a pivotal role in thapsigargin-induced apoptosis of human colon cancer HCT116 cells by controlling Smac/Diablo and Omi/HtrA2 release from mitochondria. AU - Yamaguchi,Hirohito, AU - Bhalla,Kapil, AU - Wang,Hong-Gang, PY - 2003/4/3/pubmed PY - 2003/4/23/medline PY - 2003/4/3/entrez SP - 1483 EP - 9 JF - Cancer research JO - Cancer Res VL - 63 IS - 7 N2 - Bax is a crucial mediator of the mitochondrial pathway for apoptosis, and loss of this proapoptotic Bcl-2 family protein contributes to drug resistance in human cancers. We report here that the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin (THG) induces apoptosis of human colon cancer HCT116 cells through a Bax-dependent signaling pathway controlling the cytosolic release of mitochondrial apoptogenic molecules. Treating HCT116 cells with THG results in caspase-8 activation; Bid cleavage; Bax conformational change and mitochondrial translocation; the release of cytochrome c, Smac/Diablo, and Omi/HtrA2 into the cytosol; caspase-3 activation; and apoptosis. In contrast, knockout of Bax completely abrogates the full processing/activation of caspase-3 but has no effect on the processing of caspase-8 and the initial cleavage of caspase-3 to p24 fragment after THG treatment. The caspase-8-specific inhibitor z-IETD-fmk, as well as pan-caspase inhibitor z-VAD-fmk, but not the calpain inhibitor E-64d, prevents Bid cleavage, Bax conformational change, and subsequent caspase-3 processing and apoptosis. Caspase-8 processing is dependent on de novo protein synthesis; DR5 expression is strongly up-regulated by THG treatment. Moreover, the absence of Bax blocks THG-induced Omi and Smac release from mitochondria, and expression of cytosolic Omi (GFP-IETD-Omi) or Smac (GFP-IETD-Smac) restores the sensitivity of Bax-knockout HCT116 cells to apoptosis in response to THG treatment. Taken together, our results indicate that Bax-dependent Smac and Omi release plays an essential role in caspase-3 activation and apoptosis induced by THG in human colon cancer HCT116 cells. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/12670894/Bax_plays_a_pivotal_role_in_thapsigargin_induced_apoptosis_of_human_colon_cancer_HCT116_cells_by_controlling_Smac/Diablo_and_Omi/HtrA2_release_from_mitochondria_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12670894 DB - PRIME DP - Unbound Medicine ER -