We are interested in the molecular basis of cell death and proliferation control during the genotoxic stress response. Our laboratory has focused on two tumor models: (i) Chronic lymphocytic leukemia (CLL) for leukemia, and (ii) prostate, for epithelial tumors. One project seeks to understand the DNA damage signals incurred by mammalian cells following ionizing radiation (IR). We are interested in IR-regulated genes, with a focus on those that have an important role in cell cycle checkpoints, cell proliferation, apoptosis (Bcl-2 family), and autophagy (ATG family, mTOR). The second project is focused on understanding how the three fundamental cellular responses to IR, cell cycle control, DNA repair, and cell death 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 C-terminal 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 DNA repair by preventing recruitment of accessory proteins (e.g. DNA Ligase IV, XRCC4) to the DNA repair complex assembled on double-stranded DNA, and (ii) in the cytoplasm, it dislocates BAX from Ku70 triggering BAX activation, or when expressed chronically activates autophagy leading to senescence. The third project focuses on a tumor-specific cell death ligand, Apo2L/TRAIL and its role in apoptosis, autophagy and potential for cancer therapy.
One area of focus has been to determine the molecular basis of cell death and proliferation control during the genotoxic stress response, such as encountered during chemotherapy or radiotherapy (RT) in leukemia and prostate cancer. We have been examining the DNA damage signals incurred by mammalian cells following RT. We are interested in IR-regulated genes, with a focus on those that have an important role in apoptosis, autophagy, checkpoints, and cell cycle control. Another area of interest has been the understanding of how the three fundamental cellular responses to RT: cell cycle control, DNA repair, and cell death, are integrated.
Choudhary GS, Tat T, Misra S, Hill BT, Smith MR, *Almasan A, *Mazumder S. Cyclin E/Cdk2-dependent phosphorylation of Mcl-1 determines its stability and cellular sensitivity to BH3 mimetics. Oncotarget, 2015, 6:16912-16925. (PMID: 26219338; Priority Research Paper). *corresponding authors.
Chatterjee P, Choudhary GS, Alswillah T, Xiong X, Heston WD, Magi-Galuzzi C, Zhang J, Klein EA, Almasan A. The TMPRSS2-ERG gene fusion blocks XRCC4-mediated non-homologous end joining repair and radiosensitizes prostate cancer cells to PARP inhibition. Mol Cancer Ther, 2015, 14:1896-1906. (PMID: 26026052)
Choudhary GS, Al-Harbi S, Mazumder S, Hill BT, Smith MR, Bodo J, Hsi ED, Almasan A. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/ mTORC activation in lymphoid malignancies. Cell Death & Disease, 2015, 6: e1593 (PMID: 25590803).
Rosko A, McColl, Zhong F, Chang MJ, Sattar A, Hill BT, Al-harbi S, Almasan A, Distelhorst C. Acidosis sensing receptor GPR65 correlates with anti-apoptotic Bcl-2 family member expression in CLL cells: Potential implications for the CLL microenvironment. J Leuk (Los Angel). 2014 Dec;2(5). pii: 160-166 (PMCID: PMC4431653).
Sharma A, Janocha TA, Hill BT, Smith MR, Erzurum SC, Almasan A. Targeting mTORC1-mediated metabolic addiction to overcome fludarabine resistance in malignant B cells. Molecular Cancer Res, 2014; 12:1205-1215, 2014 (article featured as a Highlight; PMC4163513).
Singh K, Sharma A, Mir MC, Drazba JA, Heston WD,Magi-Galuzzi C, Hansel D,Rubin BP, Klein EA, Almasan A. Autophagic flux determines cell death and survival in response to Apo2L/TRAIL (dulanermin). Molecular Cancer, 2014; 13:70 (highly cited; PMCID: PMC3998041).
Babcook MA, Sramkoski RM, Fujioka H, Daneshgari F, Almasan A, Shukla S, Nanavaty RR, Gupta S. Combination of simvastatin and metformin induces G1-phase cell cycle arrest and Ripk1- and Ripk3-dependent necrosis in C4-2B osseous metastatic castration-resistant prostate cancer cells. Cell Death & Disease, 2014: 5: e1536 (PMCID: PMC4260755).
Klionsky DJ, …Almasan A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 2015 (in press).
Stancu AM, Smith MR, Almasan A. New agents for the treatment of lymphoid leukemia and lymphoma: focus on recent FDA approvals. Discoveries, 2014, 2: e14 (DOI:10.15190/ d.2014.6). PMCID: PMC4535816
Singh V, Gupta D, Arora R, Tripathi RP, Almasan A, Macklis RM. Surface levels of CD20 determine anti-CD20 antibodies-mediated cell death in vitro. PLoS One. 2014, 9: e111113 (PMCID: PMC4217761).
Choudhary G, Alharbi S, Almasan A. Caspase-3 activation is a critical determinant of genotoxic stress-induced apoptosis. Methods Mol Biol, 2015; 1219:1-9 (PMID: 25308257).
Bucur O, Almasan A, et al. Discoveries: an innovative platform for publishing cutting edge research discoveries in medicine, biology and chemistry. Discoveries, 2013, 1: e1 (DOI: 10.15190/d.2013.1).
Chatterjee P, Plesca D, Mazumder S, Boutros J,Yannone SM, Almasan A. Defective chromatin recruitment and retention of NHEJ core components in human tumor cells expressing a Cyclin E fragment. Nucleic Acids Res, 2013; 41: 10157-69. (PMC3905870).
Sharma A, Singh K,Mazumder S, Hill BT, Kalaycio M, Almasan A. BECN1 and BIM interactions with MCL-1 determine fludarabine resistance in leukemic B cells. Cell Death & Disease, 2013; L4: e628 (PMC3674362).
Chatterjee P, Choudhary G, Sharma A, Singh K, Heston WD, Ciezki J, Klein EA, Almasan A. PARP inhibition radiosensitizes most effectively to low dose-rate radiation PTEN-deficient and TMPRSS2-ERG fusion gene-expressing prostate cancer cells. PloS One, 2013; 8: e60408 (PMC3614551).
Zhou N, Singh K, Mir MC, Parker Y, Lindner D, Dreicer R, Ecsedy JA, Zhang Z, The BT, Almasan A, Hansel DE. The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell cycle progression in malignant bladder cancer cells in vitro and in vivo. Clinical Cancer Res, 2013; 19: 1717-28 (PMC3626291).
Bodo J, Zhao X, Sharma A, Hill B, Portell C, Lannutti B, Almasan A, Hsi ED. The PI3K inhibitor GS-1101 synergistically potentiates HDAC inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and ERK pathways. Br J Haematol. 2013: 163:72-80 (PMC3784300).
Mazumder S, Choudhary GS, Al-harbi S, Almasan A. Mcl-1 phosphorylation defines ABT-737 resistance that can be overcome by increased NOXA expression in leukemic B-cells. Cancer Res, 2012; 72: 3069-3079 (PMC3626291).
Singh K, Matsuyama S, Drazba JA, Almasan A. Autophagy-dependent senescence in response to DNA damage and chronic apoptotic stress. Autophagy, 2012; 8: 236-51 (PMC3336077).
Qiu J, Tsien C, Thapalaya S, Narayanan A, Weihl C, Eghtesad B, Singh K, McDonald C, Almasan A, Naga Prasad SV, Dasarathy S. Hyperammonemia mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis. Am J Physiol Endocrinol Metab. 2012; 303: E983-E993 (PMC3469607).
Bucur O, Stancu AL, Khosravi-Far R, Almasan A. Analysis of apoptosis methods recently used in Cancer Research and Cell Death & Disease publications. Cell Death and Disease, 2012; e263 (PMC3288344).
Klionsky DJ, ... Almasan A. et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 2012; 8: 445–544 (PMC3404883).
Al-harbi S, Hill BT, Mazumder S, Singh K, DeVecchio J, Choudhari G, Rybicki LA, Kalaycio M, Maciejewski JP, Houghton JA, Almasan A. An anti-apoptotic Bcl-2 family expression index predicts the response of CLL to ABT-737. Blood, 2011; 118: 3579-90 (Featured in: Blood; Expert Rev. Hematology, Expert Rev. of Anticancer Therapy; PMC3186334).
Bodo J, Sedlak J, Maciejewski JP, Almasan A, Hsi ED. HDAC inhibitors potentiate the apoptotic effect of enzastaurin in lymphoma cells, Apoptosis, 2011, 16:914-23 (PMID: 21667043).