Alex Almasan, Ph.D.
Professor of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
Department of Cancer Biology
Basic mechanisms of cell death and cell cycle control, DNA damage response, radiobiology in Leukemia (CLL), and tumors of epithelial origin (prostate cancer)
We investigate the molecular basis of cell death and cell cycle control regulation and how these processes are coordinated during genotoxic stress responses, particularly following exposure to ionizing radiation. Our laboratory’s efforts are directed towards three major projects:
The first project seeks understanding of DNA damage signals incurred by mammalian cells following ionizing radiation. We study ionizing radiation-regulated genes, with a focus on those that play an important role in cell-cycle checkpoints, cell proliferation and death in hematologic and epithelial tumor cells. The second project is focused on understanding how the two fundamental cellular responses to irradiation – cell death (apoptosis, autophagy) and cell cycle control – are integrated. Our recent studies have shown that cyclin E undergoes a proteolytic, caspase-mediated cleavage during the early stages of apoptosis in hematopoietic cells. The resulting fragment of Cyclin E can no longer sustain cell-cycle regulation as it cannot bind to its catalytic partner Cdk2; instead, it binds to the DNA repair protein Ku70. As a result (i) in the nucleus it impairs recruitment and retention of NHEJ DNA repair complex components assembled on double-stranded DNA, and (ii) in the cytoplasm, it dislocates BAX from Ku70, triggering BAX activation and its translocation to mitochondria. The third project focuses on a tumor-specific cell death ligand, Apo2L/TRAIL, its role in cell death signaling and biology, and its potential for cancer therapy in epithelial and hematologic malignancies.
Chen, Q., Gong, B., Almasan, A. (2000). Distinct stages of cytochrome c release from mitochondria: a feedback amplification loop linking caspase activation to mitochondria in genotoxic stress induced apoptosis. Cell Death & Diff 7, 227-233.
Mazumder, S., Gong, B., Almasan A. (2000). Activation of cyclin E by genotoxic stress leads to apoptosis of hematopoietic cells. Oncogene 19, 2828-2835.
Gong, B. Almasan, A. (2000). Apo2L/TRAIL and DR5 mediate apoptotic signaling by ionizing radiation in leukemic cells. Cancer Res 60, 5754-5760.
Chen, Q., Gong, B, Mahmoud-Ahmed, A., Zhou, A., Hussein, M., Almasan, A. (2001). Induction of Apo2L and modulation of Bcl-2-related proteins regulate Type I interferon-induced apoptosis in multiple myeloma. Blood 98, 2183-2192.
Mazumder, S., Gong, B., Chen, Q., Drazba, J., Buchsbaum, J., Almasan, A. (2002). Proteolytic cleavage of Cyclin E leads to inactivation of associated kinase activity and amplification of apoptosis in hematopoietic cells. Mol Cell Biol 22, 2398-2409.
Chen, Q., Chai, Y., Mazuder, S., Jiang, C, Macklis, R.M., Chisolm, G.M., Almasan A. (2003). The late increase in free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction. Cell Death & Diff 10, 323-334.
Almasan A., Ashkenazi, A. (2003). Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokines Growth Factor Rev 14, 337-348.
Ray, S., Almasan, A. (2003). Apoptosis induction in prostate cancer cells and xenografts by combined treatment with Apo2L/TRAIL and CPT-11. Cancer Res 63, 4713-4723.
DuPree E.L., Mazumder S., Almasan A. (2004). Genotoxic stress induces expression of E2F4, leading to its association with p130 in prostate carcinoma cells. Cancer Res 64, 4390-3.
Ray, S., Bucur, O., Almasan, A. (2005). Sensitization of prostate carcinoma cells to Apo2L/TRAIL by a Bcl-2 Family Inhibitor. Apoptosis 10, 1411-1418.
Crosby, M.E., Jacobberger, J., Gupta, D., Macklis, R.M., Almasan, A. (2007). E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma. Oncogene 26,1897-909.
Mazumder, S., Plesca, D., Kinter, M., Almasan A. (2007). Interaction of a Cyclin E fragment with Ku70 regulates Bax-mediated apoptosis in hematopoietic cells. Mol Cell Biol 27, 3511-3520.
Ray, S. Shyam, S, Frazier, G., Almasan A. (2007). S-phase checkpoints regulate Apo2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand and CPT-11-induced apoptosis of prostate cancer cells. Mol Cancer Ther 6, 1368-1378
Plesca, D., Crosby, M.E, Gupta, D., Almasan, A. (2007). E2F4 Function in G2: Maintaining G2-arrest to prevent mitotic entry with damaged DNA. Cell Cycle 6, 1147-52.
Mazumder, S., Plesca, D., Almasan A. (2007). A Jekyll and Hyde role of Cyclin E in the genotoxic stress response: Switching from cell cycle control to apoptosis regulation. Cell Cycle. 6, 1437-1442.
Mazumder, S., Plesca, D., Almasan, A. (2008). Caspase-3 activation as a critical determinant of genotoxic stress-induced apoptosis. Methods Mol Biol 414, 13-21.
Mazumder, S., Plesca, D., Almasan, A. (2008). DNA damage-induced apoptosis. Methods Enzymol 446:107-122.
Gupta, D., Crosby, M.E, Almasan, A., Macklis, R.M. (2008). Regulation of CD20 expression by radiation-induced changes in intracellular redox milieu. Free Radicals in Biol Med 44:614-623.
Plesca D., Mazumder S., Gama V., Matsuyama S., Almasan A. (2008). A C-terminal fragment of Cyclin E, generated by caspase-mediated cleavage, is degraded in the absence of a recognizable phosphodegron. J Biol Chem 283:30796-30803.
Singh K., Eisermann K., Piontkivska H., Frazier G., Almasan A. (2009). Common signaling pathways in prostate cancer: importance of coordinate gene regulation. In: "Prostate Cancer Cells: Growth, Signaling, and Survival," Ed: Columbus F., NOVA Publishers, Hauppauge, NY.
Boutros J., Almasan A. (2009). Combining 2-deoxy-D-glucose with electron transport chain blockers: a double-edged sword. Cancer Biol Ther 8:1237-1238.
Neznanov N., Gorbachev A.V., Neznanova L., Komarov A.P., Gurova K.V., Gasparian A.V., Banerjee A.K., Almasan A., Fairchild R.L., Gudkov A.V. (2009). Anti-malaria drug blocks proteotoxic stress response: anti-cancer implications. Cell Cycle. 8: 3960-3970.
Khan, F., Khan MK, Almasan, A., Singh, A.D., Macklis, R.M. (2011). The evolving role of radiation therapy in the management of malignant melanoma. Int J Radiat Oncol Biol Phys 80, 645-654.
Bodo, J., Sedlak, J., Maciejewski, J.P., Almasan, A., Hsi, E.D. (2011). HDAC inhibitors potentiate the apoptotic effect of enzastaurin in lymphoma cells. Apoptosis 16:914-923.
Al-harbi, S., Hill, B.T., Mazumder, S., Singh, K., DeVecchio, J., Choudhari, G., Rybicki, L.A., Kalaycio, M., Maciejewski, J.P., Houghton, J.A., Almasan A. (2011). An anti-apoptotic Bcl-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737. Blood 118:3579-3590.
Khan, M.K., Khan, F., Almasan, A., Macklis, R.M. (2011). The future of radiation therapy for malignant melanoma. OncoTargets and Therapy. 4:137-148.
Sharma, A., Kamini, S., Almasan, A. (2012). Gamma-H2AX as a marker for the DNA damage response. Methods Mol Biol, Vol. 920 (in press).
Mazumder S, Choudhary GS, Al-harbi S, Almasan A. (2012). Mcl-1 phosphorylation defines ABT-737 resistance that can be overcome by increased NOXA expression in leukemic B-cells. Cancer Res 72:3069-79.
Singh K, Matsuyama S, Drazba JA, Almasan A. (2012). Autophagy-dependent senescence in response to DNA damage and chronic apoptotic stress. Autophagy. 8:236-51.
Klionsky DJ, … Almasan A, et al. (2012). Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 8: 445 - 544.