Subrata Haldar, Ph.D.
Rammelkemp Center for
Education and Research
MetroHealth Medical Center
2500 MetroHealth Dr.
Cleveland, Ohio 44109-1998
Phone: (216) 778-1167
Fax: (216) 778-4321
Cancer cells forget to die by the ability to keep them away from committing suicide
by a delicate cellular process called "Apoptosis." This ability of cancer cells
to evade apoptosis or programmed cell death is one of the keys for their fight against
attack from chemo- or radiation therapy. The focus of our research program is to
find ways to make these cancer cells sensitive to suicide. Our long-term goal is
to develop apoptosis inducing therapy for chemoresistant malignant tumors.
Bcl2 (B cell lymphoma and leukemia-2) gene is the founding member of a large family
of inhibitors and activators of apoptosis. Bcl2-like proteins (Bcl-xL/Mcl-1) play
an essential role in controlling apoptosis. Consequently, deregulation of these
proteins can contribute to diseases, most notably to cancer. Despite a major research
effort, how Bcl2-like proteins control apoptosis is still a highly debated topic.
As phosphorylation is a common way of regulating protein function, the discovery
of Bcl2 phosphorylation is a very intriguing observation. We are poised to understand
how phosphorylation of Bcl-2/Bcl-xL can regulate the development of B-lymphocytes
using transgenic model developed in the laboratory.
Another objective of our research program is to explore the basis for the endocrine
treatment of human pancreatic cancer. Carcinoma of the pancreas is one of the most
aggressive human malignancies, with an extremely poor prognosis. Irradiation and
cytotoxic chemotherapy alone or in combination have only a minor influence on survival.
Pancreatic cancer cells are usually resistant to conventional apoptosis-inducing
agents. A new treatment strategy in handling pancreatic tumors is the use of endocrine
treatment. In our laboratory, we have studied the effect of an endogenous estrogen
metabolite 2-methoxyestradiol (2-ME) on programmed cell death in human pancreatic
cancer cells. Using cDNA microarray analysis as well as preclinical animal model,
our research will be directed towards unraveling the potential downstream effector
of 2-ME triggered apoptotic signaling pathway in pancreatic cancer.
Basu, A. and Haldar, S. (2003) Identification of a novel Bcl-xL phosphorylation
site regulating the sensitivity of Taxol or 2-Methoxyestradiol induced apoptosis.
FEBS Lett. 538: 41-47.
Basu, A., Das, M., Qanungo, S., Fan, X-U, Dubois, G. and Haldar, S. (2002)
Proteasomal Degradation of Human Peptidyl Prolyl Isomerase Pin 1-Pointing Phospho
Bcl2 towards Dephosphorylation. Neoplasia 4: 218 - 227.
Haldar, S., Basu, A. and Croce, C.M (1998) Serine-70 is one of the critical
sites for drug-induced Bcl2 phosphorylation in cancer cells. Cancer Res. 58: 1609-1615.
Haldar, S., Jena, N. and Croce, C.M. (1995) Inactivation of Bcl2 by phosphorylation.
Proc. Natl. Acad. Sci. USA 92 : 4507-4511.
Qanungo, S., Basu, A., Das, M. and Haldar, S. (2002) 2-Methoxyestradiol elicits
mitochondria dependent apoptotic signaling in Pancreatic cancer cells. Oncogene.