Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2008

Open Access 01-12-2008 | Research

The Involvement of Bax in Zinc-Induced Mitochondrial Apoptogenesis in Malignant Prostate Cells

Authors: Pei Feng, Tieluo Li, Zhixin Guan, Renty B Franklin, Leslie C Costello

Published in: Molecular Cancer | Issue 1/2008

Login to get access

Abstract

Background

The development and progression of prostate cancer requires the transformation of normal zinc-accumulating epithelial cells to malignant cells that have lost the ability to accumulate zinc. This metabolic transformation is essential so that the tumor suppressive effects of zinc can be eliminated and the malignant process can proceed. One of the major effects of zinc is its prevention of prostate cell growth by its induction of apoptosis. The accumulation of cellular zinc has a direct effect on the mitochondria that results in the release of cytochrome c, which initiates the caspase cascade that leads to apoptosis. This effect is associated with the mitochondrial pore-forming process, but the mechanism by which zinc induces the release of cytochrome c and induces mitochondrial apoptogenesis has not been resolved. The present report provides for the first time information that implicates Bax in the zinc induction of mitochondrial apoptogenesis.

Results

The effects of zinc treatment on the Bax levels of PC-3 cells and on the mitochondria were determined. The exposure of isolated mitochondria to zinc results in an increase in membrane bound Bax, which is due to the mitochondrial insertion of endogenous resident Bax. The mitochondrial Bax/Bcl-2 ratio is increased by zinc treatment. Zinc treatment of PC-3 cells also increases the mitochondrial level of Bax. In addition, zinc treatment increases the cellular level of Bax and the cellular Bax/Bcl2 ratio. Down regulation of Bax in PC-3 cells eliminates the zinc induction of apoptosis. The increase in cellular Bax level appears to involve zinc induction of Bax gene expression.

Conclusion

This report extends and confirms that physiological levels of zinc induce apoptosis in prostate cells. The study provides evidence that zinc is directly involved in facilitating a Bax-associated pore formation process that initiates mitochondrial apoptogenesis. This is enhanced by an additional effect of zinc on increasing the cellular level of Bax. To avoid the anti-tumor apoptogenic effects of zinc, the malignant cells in prostate cancer posses genetic/metabolic adaptations that prevent the cellular accumulation of zinc.
Appendix
Available only for authorised users
Literature
1.
Costello LC, Franklin RB: The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots. Mol Cancer. 2006, 15: 5-17.
2.
Franklin RB, Milon B, Feng P, Costello LC: Zinc and zinc transporter in normal prostate function and the pathogenesis of prostate cancer. Frontiers in Bioscience. 2005, 10: 2230-2239.PubMedCentralCrossRefPubMed
3.
4.
Franklin RB, Zou J, Costello LC: Effect of zinc on proliferation of prostate cancer cells. Urol Res. 1995, 23: 266-
5.
Liang J-Y, Liu Y-Y, Zou J, Franklin RB, Costello LC, Feng P: Inhibitory effect of zinc on human prostatic carcinoma cell growth. Prostate. 1999, 40: 200-207.PubMedCentralCrossRefPubMed
6.
Feng P, Liang J-Y, Li T-L, Guan Z-X, Zou J, Franklin RB, Costello LC: Zinc induces mitochondria apoptogenesis in prostate cells. Mol Urology. 2000, 4: 31-36.
7.
Feng P, Li T-L, Guan Z-X, Franklin RB, Costello LC: Direct effect of zinc on mitochondrial apoptogenesis in prostate cells. Prostate. 2002, 52: 311-318.PubMedCentralCrossRefPubMed
8.
Antignani A, Youle RJ: How do Bax and Bak lead to permeabilization of the outer mitochondrial membrane?. Curr Opin Cell Biol. 2006, 18: 685-689.CrossRefPubMed
9.
Dejean LM, Martinez-Caballero S, Guo L, Hughes C, Teijido O, Ducret T, Ichas F, Korsmeyer SJ, Antonsson B, Jonas EA, Kinnally KW: Oligomeric Bax is a component of the putative cytochrome c release channel MAC, mitochondrial apoptosis-induced channel. Mol Biol Cell. 2005, 16: 2424-2432.PubMedCentralCrossRefPubMed
10.
Suzuki M, Youle RL, Tjandra N: Structure of Bax: co-regulation of dimer formation and intracellular localization. Cell. 2000, 103: 645-654.CrossRefPubMed
11.
Yamaguchi H, Wang HG: Bcl-XL protects BimEL-induced Bax conformational change and cytochrome C release independent of interacting with Bax or BimEL. J Biol Chem. 2002, 277: 41604-41612.CrossRefPubMed
12.
Korsmeyer SJ: Bcl-2 gene family and the regulation of programmed cell death. Cancer Res. 1999, 59: 1693s-1700s.PubMed
13.
Park SE, Park JW, Cho YS, Ryu JH, Paick JS, Chun YS: HIF-1alpha promotes survival of prostate cells at a high zinc environment. Prostate. 2007, 67: 1514-1523.CrossRefPubMed
14.
Uzzo RG, Leavis P, Hatch W, Gabai VL, Dulin N, Zvartau N, Kolenko VM: Zinc inhibits nuclear factor-kappa B activation and sensitizes prostate cancer cells to cytotoxic agents. Clin Cancer Res. 2002, 8: 3579-3583.PubMed
15.
Bae SN, Lee YS, Kim MY, Kim JD, Park LO: Antiproliferative and apoptotic effects of zinc-citrate compound (CIZAR(R)) on human epithelial ovarian cancer cell line, OVCAR-3. Gynecol Oncol. 2006, 103: 127-136.CrossRefPubMed
16.
Bae SN, Kim J, Lee YS, Kim JD, Kim MY, Park LO: Cytotoxic Effect of Zinc-Citrate Compound on Choriocarcinoma Cell Lines. Placenta. 2007, 28: 22-30.CrossRefPubMed
17.
Fong LY, Nguyen VT, Farber JL: Esophageal cancer prevention in zinc deficient rats: rapid induction of apoptosis by replenishing zinc. J Natl Cancer Inst. 2001, 93: 1525-1533.CrossRefPubMed
18.
Park JA, Koh JY: Induction of an immediate early gene egr-1 byzinc through extracellular signal-regulated kinase activation in cortical culture: its role in zinc-induced neuronal death. J Neurochem. 1999, 73: 450-456.CrossRefPubMed
19.
Falke D, Fisher M, Ye D, Juliano RL: (2003) Design of artificial transcription factors to selectively regulate the pro-apoptotic bax gene. Nucleic Acids Res. 2003, 31: e10-PubMedCentralCrossRefPubMed
20.
Franklin RB, Feng P, Milon BC, Desouki MM, Singh KK, Kajdacsy-Balla A, Bagasra O, Costello LC: hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer. Mol Cancer. 2005, 4: 32-PubMedCentralCrossRefPubMed
21.
Desouki MM, Geradts J, Milon B, Franklin RB, Costello LC: hZip2 and hZip3 zinc transporters are down regulated in human prostate adenocarcinomatous glands. Mol Cancer. 2007, 6: 37-PubMedCentralCrossRefPubMed
22.
Feng P, Li TL, Guan ZX, Franklin RB, Costello LC: Effect of zinc on prostatic tumorigenicity in nude mice. Ann N Y Acad Sci. 2003, 1010: 316-320.CrossRefPubMed
23.
Rudolf E, Rudolf K, Cervinka M: Zinc-induced apoptosis in HEP-2 cancer cells: the role of oxidative stress and mitochondria. Biofactors. 2005, 23: 107-120.CrossRefPubMed
24.
Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976, 72: 248-254.CrossRefPubMed
25.
Eskes R, Desagher S, Antonsson B, Martinou JC: Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Molecular and Cellular Biology. 2000, 20 (3): 929-935.PubMedCentralCrossRefPubMed
Metadata
Title
The Involvement of Bax in Zinc-Induced Mitochondrial Apoptogenesis in Malignant Prostate Cells
Authors
Pei Feng
Tieluo Li
Zhixin Guan
Renty B Franklin
Leslie C Costello
Publication date
01-12-2008
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2008
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-7-25

Other articles of this Issue 1/2008

Molecular Cancer 1/2008 Go to the issue

Research

Identification and transcript analysis of a novel wallaby (Macropus eugenii) basal-like breast cancer cell line

Research

Reduction of human chorionic gonadotropin beta subunit expression by modified U1 snRNA caused apoptosis in cervical cancer cells

Research

Membrane androgen receptor activation triggers down-regulation of PI-3K/Akt/NF-kappaB activity and induces apoptotic responses via Bad, FasL and caspase-3 in DU145 prostate cancer cells

Review

DNA methylation-based biomarkers for early detection of non-small cell lung cancer: an update

Research

Rac1 GTPase and the Rac1 exchange factor Tiam1 associate with Wnt-responsive promoters to enhance beta-catenin/TCF-dependent transcription in colorectal cancer cells

Research

Differential effects of class I isoform histone deacetylase depletion and enzymatic inhibition by belinostat or valproic acid in HeLa cells
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits