BAD-mediated apoptotic pathway is associated with human cancer development

Stickles,Xiaomang B.; Marchion,Douglas C.; Bicaku,Elona; Al Sawah,Entidhar; Abbasi,Forough; Xiong,Yin; Bou Zgheib,Nadim; Boac,Bernadette  M.; Orr,Brian  C.; Judson,Patricia  L.; Berry,Amy; Hakam,Ardeshir; Wenham,Robert  M.; Apte,Sachin  M.; Berglund,Anders  E.; Lancaster,Johnathan  M.

doi:10.3892/ijmm.2015.2091

April-2015 Volume 35 Issue 4

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

April-2015 Volume 35 Issue 4

Full Size Image

Article

BAD-mediated apoptotic pathway is associated with human cancer development

Authors:
- Xiaomang B. Stickles
- Douglas C. Marchion
- Elona Bicaku
- Entidhar Al Sawah
- Forough Abbasi
- Yin Xiong
- Nadim Bou Zgheib
- Bernadette M. Boac
- Brian C. Orr
- Patricia L. Judson
- Amy Berry
- Ardeshir Hakam
- Robert M. Wenham
- Sachin M. Apte
- Anders E. Berglund
- Johnathan M. Lancaster
View Affiliations / Copyright

Affiliations: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA, Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA, Cancer Informatics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
Pages: 1081-1087
|
Published online on: February 5, 2015

https://doi.org/10.3892/ijmm.2015.2091
Expand metrics +

Abstract

The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair. Evidence suggests that the Bcl-2 antagonist of cell death (BAD)-mediated apoptotic pathway influences cancer chemoresistance. In the present study, we explored the role of the BAD-mediated apoptotic pathway in the development and progression of cancer. Using principal component analysis to derive a numeric score representing pathway expression, we evaluated clinico-genomic datasets (n=427) from corresponding normal, pre-invasive and invasive cancers of different types, such as ovarian, endometrial, breast and colon cancers in order to determine the associations between the BAD-mediated apoptotic pathway and cancer development. Immunofluorescence was used to compare the expression levels of phosphorylated BAD [pBAD (serine-112, -136 and -155)] in immortalized normal and invasive ovarian, colon and breast cancer cells. The expression of the BAD-mediated apoptotic pathway phosphatase, PP2C, was evaluated by RT-qPCR in the normal and ovarian cancer tissue samples. The growth-promoting effects of pBAD protein levels in the immortalized normal and cancer cells were assessed using siRNA depletion experiments with MTS assays. The expression of the BAD-mediated apoptotic pathway was associated with the development and/or progression of ovarian (n=106, p<0.001), breast (n=185, p<0.0008; n=61, p=0.04), colon (n=22, p<0.001) and endometrial (n=33, p<0.001) cancers, as well as with ovarian endometriosis (n=20, p<0.001). Higher pBAD protein levels were observed in the cancer cells compared to the immortalized normal cells, whereas PP2C gene expression was lower in the cancer compared to the ovarian tumor tissue samples (n=76, p<0.001). The increased pBAD protein levels after the depletion of PP2C conferred a growth advantage to the immortalized normal and cancer cells. The BAD-mediated apoptotic pathway is thus associated with the development of human cancers likely influenced by the protein levels of pBAD.

View Figures

View References

1	Marone M, Scambia G, Mozzetti S, et al: bcl-2, bax, bcl-XL, and bcl-XS expression in normal and neoplastic ovarian tissues. Clin Cancer Res. 4:517–524. 1998.PubMed/NCBI
2	Llambi F and Green DR: Apoptosis and oncogenesis: give and take in the BCL-2 family. Curr Opin Genet Dev. 21:12–20. 2011. View Article : Google Scholar : PubMed/NCBI
3	Chon HS, Marchion DC, Xiong Y, et al: The BCL2 antagonist of cell death pathway influences endometrial cancer cell sensitivity to cisplatin. Gynecol Oncol. 124:119–124. 2012. View Article : Google Scholar
4	Marchion DC, Cottrill HM, Xiong Y, et al: BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival. Clin Cancer Res. 17:6356–6366. 2011. View Article : Google Scholar : PubMed/NCBI
5	Tan Y, Demeter MR, Ruan H and Comb MJ: BAD Ser-155 phosphorylation regulates BAD/Bcl-XL interaction and cell survival. J Biol Chem. 275:25865–25869. 2000. View Article : Google Scholar : PubMed/NCBI
6	Hayakawa J, Ohmichi M, Kurachi H, et al: Inhibition of BAD phosphorylation either at serine 112 via extracellular signal-regulated protein kinase cascade or at serine 136 via Akt cascade sensitizes human ovarian cancer cells to cisplatin. Cancer Res. 60:5988–5994. 2000.PubMed/NCBI
7	Zha J, Harada H, Yang E, Jockel J and Korsmeyer SJ: Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell. 87:619–628. 1996. View Article : Google Scholar : PubMed/NCBI
8	Yang E, Zha J, Jockel J, Boise LH, Thompson CB and Korsmeyer SJ: Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell. 80:285–291. 1995. View Article : Google Scholar : PubMed/NCBI
9	Hirai I and Wang HG: Survival-factor-induced phosphorylation of Bad results in its dissociation from Bcl-x(L) but not Bcl-2. Biochem J. 359:345–352. 2001. View Article : Google Scholar : PubMed/NCBI
10	del Peso L, González-García M, Page C, Herrera R and Nunez G: Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science. 278:687–689. 1997. View Article : Google Scholar : PubMed/NCBI
11	Lizcano JM, Morrice N and Cohen P: Regulation of BAD by cAMP-dependent protein kinase is mediated via phosphorylation of a novel site, Ser155. Biochem J. 349:547–557. 2000. View Article : Google Scholar : PubMed/NCBI
12	Zhou XM, Liu Y, Payne G, Lutz RJ and Chittenden T: Growth factors inactivate the cell death promoter BAD by phosphorylation of its BH3 domain on Ser155. J Biol Chem. 275:25046–25051. 2000. View Article : Google Scholar : PubMed/NCBI
13	Klumpp S, Selke D and Krieglstein J: Protein phosphatase type 2C dephosphorylates BAD. Neurochem Int. 42:555–560. 2003. View Article : Google Scholar : PubMed/NCBI
14	Bansal N, Marchion DC, Bicaku E, et al: BCL2 antagonist of cell death kinases, phosphatases, and ovarian cancer sensitivity to cisplatin. J Gynecol Oncol. 23:35–42. 2012. View Article : Google Scholar : PubMed/NCBI
15	Youle RJ and Strasser A: The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 9:47–59. 2008. View Article : Google Scholar
16	Ma XJ, Salunga R, Tuggle JT, et al: Gene expression profiles of human breast cancer progression. Proc Natl Acad Sci USA. 100:5974–5979. 2003. View Article : Google Scholar : PubMed/NCBI
17	Jolliffe IT: Principal Component Analysis. 2nd edition. Springer; New York: pp. p4882002
18	Hanahan D and Weinberg RA: Hallmarks of cancer: the next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
19	Datta SR, Katsov A, Hu L, et al: 14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphory-lation. Mol Cell. 6:41–51. 2000. View Article : Google Scholar : PubMed/NCBI
20	Virdee K, Parone PA and Tolkovsky AM: Phosphorylation of the pro-apoptotic protein BAD on serine 155, a novel site, contributes to cell survival. Curr Biol. 10:R8832000. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

BAD-mediated apoptotic pathway is associated with human cancer development

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Related Articles