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Research Interests:
Translational Cancer Research Program:
The focus of the laboratory is to translate the understanding of cell death regulation in cancer cells to molecular targeted therapy for cancer.
Background:
Normally within a cell there is a balance between cell death and cell survival. Cells in an appropriate environment, with no stress, and/or undamaged will survive. Cells taken out of their appropriate environment, under stressful conditions, and/or damaged will undergo cell death (apoptosis). In cancer, this balance is altered where cell survival responses are increased preventing a cancer cells to undergo apoptosis. Understanding the decision mechanisms within cells that decide to induced apoptosis or survive will provide insight into why cancer cells survive and lead to molecular targets for cancer treatment. My research can be subdivided into three types of cancers that have altered the balance between cell death and survival
A
cancer cells dying under low oxygen conditions (hypoxia)
A) Glioblastoma multiforme (Brain cancer)
Glioblastoma multiforme (GBM) is an aggressive form of cancer where patients survive less than two years after diagnosis. These tumors have altered the balance between cell survival and cell death to the point where cells survival under low oxygen conditions. These areas of hypoxia (low oxygen) correspond to poor prognosis. A pro-cell death Bcl-2 family member, BNIP3 that was discovered in our Institute, is up-regulated in hypoxic regions of GBM tumors. We have discovered that BNIP3 contributes to cell death under hypoxia and this is blocked by growth factors such as epidermal growth factor (EGF) and Bcl-2 anti-apoptotic family members. We also discovered that BNIP3 is localized to the nucleus where it represses the expression of anti-apoptotic proteins. In addition, BNIP3 induces an autophagy response in cells that contributes to both cell survival and cell death. We are currently determining the whether BNIP3 is a good prognostic marker for GBM tumors for response to therapy and whether it is a good target for chemotherapy.
Supported in the past by CancerCare Manitoba Foundation and Canadian Institutes for Health Research.
Publications:
Kothari, S, Cizeau, J., McMillian-Ward, E., Isreals, S., Ens K., Kirshenbaum, L., Bailes, M., and
Gibson, S.B. 2003 BNIP3 plays a role in hypoxia induced cell death and is negatively regulated by growth factors in human epithelial-derived cells. Oncogene 22: 4734-4744
Burton, T.R., Henson, E.S., Baijal, P., Eisenstat, D.D. and Gibson, S.B. 2006 The pro-cell death Bcl-2 family member, BNIP3, is localized in the nucleus of human glial cells: Implications for glioblastoma multiforme tumor cell survival under hypoxia. Int. J. Cancer 118:1660-9
Burton, T, Eisenstat, D. D. and Gibson S.B. 2009 Bcl-2 Nineteen kilodalton Interacting Protein (BNIP3) acts as transcriptional repressor of Apoptosis Inducing Factor (AIF) expression preventing cell death in human malignant gliomas. J. Neuroscience 29:4189-99.
B) Breast Cancer
Breast cancer is the one the most common forms of cancer affecting women in Canada with many women surviving past five years. Breast tumors have altered the balance between cell survival and cell death through dysregulation of the estrogen and EGF signaling pathways. We have discovered that EGF up-regulates an anti-apoptotic protein called Mcl-1 in breast tumors leading to resistance to EGF receptor targeted therapies and standard chemotherapy for breast cancer. The signal transduction pathways regulating this increase is under investigation that will hopefully lead to more effective targeted therapies.
Supported in the past by Canadian Breast Cancer Foundation and Canadian Institute for Health Research
Publications:
Gibson, E. M., Henson, E.S., Villenaeuva, J., Haney, N., and Gibson S. B. 2002 Epidermal growth factor protects epithelial cells from TRAIL-induced apoptosis mediated by AKT/PKB activation. Cancer Research 62:488-496
Henson, H.S., Hu, X., and Gibson, S.B. 2006 Herceptin sensitizes ErbB2 (Her2/neu) over expressing cells to apoptosis by reducing anti-apoptotic Mcl-1 expression. Clinical Cancer Research 12:845-53.
Azad M. B., Chen Y., Henson E. S., McMillian Ward E., Israels S. J., and
Gibson S. B. 2008 Hypoxia induces autophagic cell death in apoptosis-competent cancer cells. Autophagy 4:195-204
C) Chronic Lymphocytic Leukemia (Blood cancer)
Chronic Lymphocytic Leukemia (CLL) is a B cell malignancy that is incurable. Many patients survive for many years (greater than 10 years) but eventually succumb to their disease. Since CLL cells in the blood fail to proliferate, the balance between cell survival and cell death is profoundly altered. We have found that older CLL patients have a worse relative survival outcome compared to younger patients. These patients also fail to respond to therapy as well. These older patients have higher inflammatory cytokine levels and shorter telomeres in their DNA. We are currently investigator whether these factors increase survival in CLL cells. In addition, a lipid receptor called LPA1 is up-regulated in a sub-set of patients and upregulates cytokines and increased cell survival in CLL cells. We are currently investigating whether this receptor is a good target for CLL therapy.
Supported in the past by Leukemia and Lymphoma Society
Publications:
Johnston, J. B., Kabore, A. F., Strutinsky, J., Hu, X., Paul, J. T., Kuschak B., Begleiter A, and
Gibson, S. B., 2003 Role of TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis of primary chronic lymphocytic leukemia (CLL) cells. Oncogene 22:8356-8369
Shetty, S., Graham, B.A., Brown, J.G., Paul, J.T., Harding, G, Vegh-Yarma, N., Hu, X., and
Gibson, S.B. 2005 Transcription factor NFB differentially regulates death receptor 5 (DR5) expression involving HDAC1. Mol. Cell. Biol. 25:5404-16
Ishdorj, G., Graham, B., Hu, X., Johnston, J. B., Chen, J., Fang, X., and
Gibson, S. B. 2008 Lysophosphatidic acid (LPA) protects cancer cells from HDAC inhibitor induced apoptosis mediated by histone deacetylase (HDAC) activation. J. Biol. Chem. 283:16818-29
Impact on Manitoba, Canada and the World
Through the understanding of the regulation that decides whether cells undergo cell death or cell survival, molecular targets for cancer treatment can be developed. We are currently investigating two drugs used in clinical trails for cancer treatment and have initiated another clinical trial in Manitoba using a drug that targets both death pathways and survival pathways. We are developing a Canadian network of CLL researchers with the goal of increasing clinical trails in CLL within Canada. We are also developing a translational research program where all cancerous tissue will be collected for research. This will be networked with other tissue Banks across Canada. Finally, through our research efforts we have established connections with research groups in United States and England to develop our research program. Our goal is to have a translational research program where our discoveries will be translated into the clinical setting and from the clinical setting new research questions will be developed. Our motto is from the benchside to the bedside and back again.
Recent Publications:
PubMed
Listed Publications
Lab Members:
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