Department of Cancer Biology

	Molecular and Cellular Oncology Department
	Cancer Biology Program
	Cellular Genetics Laboratory

Research Interests

Our research is concerned with determining how apoptosis (programmed cell death) is altered during tumor progression, especially in metastatic cells. Alterations in cell cycle control often lead not only to increased cell proliferation but also to increased propensity to undergo apoptosis, and tumor cells develop specific mechanism(s) to suppress this cell death. The latter may also interfere with anti-tumor therapy, because most (if not all) current strategies to treat cancer can initiate apoptosis in tumor cells. Therefore, identifying these cell death resistance mechanisms appears critical to the development of better cancer therapies.

In one project we are investigating how apoptosis is suppressed in B lymphocytes from patients with chronic lymphocytic leukemia (CLL). These cells accumulate to very high numbers in the peripheral blood of CLL patients, despite exhibiting very low levels of cell division. Thus, CLL is probably a disease of decreased cell death rather than increased cell division. Our work indicates that signal transduction pathways involving protein kinase C (PKC), protein kinase B/AKT, and the transcription factor, NFkB, are critically important in regulating CLL cell survival. Conversely, we have identified a class of new therapeutic agents (proteasome inhibitors) that trigger apoptosis in all CLL cells analyzed to date. Our work helped to prompt a clinical (Phase I) trial using proteasome inhibitors in leukemia to be held here at M.D. Anderson. This trial will allow us to directly analyze the effects of proteasome inhibitors on induction of apoptosis in patients treated with this class of drugs in vivo, and it will enable us to confirm or dispel the idea that the signaling pathways described above are important targets in the response.

In a second project we are analyzing the regulation of apoptosis in metastatic tumor cells. Metastatic variants of human prostate, pancreatic, and colon cancer display very specific defects in the control of apoptosis that appear to contribute substantially to their overall biological behavior. In prostate cancer, the metastatic variants become independent of male sex steroid (testosterone) for their growth and survival, effects that are linked to overexpression of the anti-apoptotic protein, BCL-2. Interestingly, our collaborative work with Dr. Curtis Pettaway indicates that BCL-2 directly promotes the activity of the receptor for testosterone, even when testosterone is not available to the cells. BCL-2 may also play an important role in pancreatic cancer progression, where it dramatically enhances tumorigenicity and angiogenesis via a mechanism involving the transcription factor, NFkB. Finally, in collaboration with Dr. Gary Gallick, we have found that metastatic human colon cancer cells display a very specific resistance to a specialized form of apoptosis, known as "anoikis", that occurs when tumor cells detach from neighboring cells or extracellular matrix. Interestingly, this resistance does not involve BCL-2 or its closely related structural homologues, but it does involve at least two different protein kinases (Src and AKT) which appear to act in a cell type-specific manner. Identifying the substrates for these kinases that mediate cell death suppression is an area of intensive investigation in the laboratory.

Selected References

1) Chandra, J. Gilbreath, J. Freireich, E.J. Kliche, K.O. Andreff, M. Keating, M and McConkey, J.J. Protease activation is required for glucocorticoid-induced apoptosis in chronic lymphocytic leukemic lympohcytes. Blood 90: 3673-3681 (1997).

2) Chandra, J. Niemer, i. Gilbreath, J. Kliche, K.O., Andreeff, M. Freireich, e.j. Keating, M and McConkey, D.J. Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lympohcytes, Blood 92: 4220-4229 (1998)

3) McConkey, D.J. Greene, G. and Pettaway, C.A. Apoptosis resistance increases with metastatic potential in cells of the human LNCaP prostate carcinoma line, Cancer Research in press.

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