Hector Biliran received his Ph.D. in the Molecular and Cellular Pathobiology program of Wayne State University, Department of Pathology, Detroit, MI in Dec., 2007. His graduate work which involved elucidating the molecular mechanism underlying the tumor suppressive function of maspin received the Scholar-In-Training Award from the American Association for Cancer Research (AACR). Following his graduate work, the PI focused on establishing his cancer research expertise on the molecular mechanisms and regulators of cancer cell survival and apoptosis. While working as a Post-doctoral Research Fellow in the laboratory of Dr Joshua Liao and Dr. Fazlul Sarkar at the Karmanos Cancer Institute, the P.I. was instrumental in identifying two oncogenes, cyclin D1 and c-myc, as important regulators of pancreatic cancer growth, survival, and chemosensitivity. To expand his knowledge on the mechanism(s) of the apoptotic process, the PI pursued further post-doctoral research work in the laboratory of Dr. Erkki Ruoslahti at the NCI-designated Cancer Center, Sanford-Burnham Medical Research Institute, examining the novel Bcl2-inhibitor of transcription (Bit1) caspase-independent apoptotic pathway. The PI is an associate member of the Associate Member, American Association for Cancer Research (AACR) and Louisiana Cancer Research Consortium (LCRC).
A Potential Role of Bcl2-inhibitor of transcription (Bit1) in the Induction of Apoptosis and Chemosensitization of Highly Aggressive Cancer Cells
Highly aggressive cancer cells often are associated with resistance to caspase-dependent apoptosis, due in part to loss in function or mutation in caspase effectors. Such apoptotic defects in caspase signaling may provide a selective growth advantage for tumor cells and potentiate their aggressiveness and resistance to cell death or apoptosis. The major challenge therefore in combating and halting the growth of aggressive cancer cells is to find new modalities that can potently induce apoptosis in cancer cells such as through induction of the alternative caspase-independent apoptotic pathway. The goal of this project is to examine the role of the novel caspase-independent apoptotic effector, Bcl2-inhibitor of transcription (Bit1), in the apoptosis resistance and survival of cancer cells. Bit1 is a mitochondrial protein that is released to the cytosol following loss of cell attachment, and subsequently induces a caspase-independent apoptosis. We hypothesize that the caspase-independent apoptotic effector Bit1 is an important alternate cell death pathway that may be activated to induce apoptosis and attenuate the enhanced survival of cancer cells, and render cancer cells more susceptible to the killing effect of chemotherapeutic agents. Data derived from these studies will shed information regarding the apoptotic networks in the highly metastatic and chemoresistant cancer cells. We believe that activation of the caspase-independent cell death pathway via the Bit1 apoptotic function will result in a more successful eradication of chemoresistance. Bit-1, as a caspase-independent apoptotic effector, may serve as a novel therapeutic target for the treatment of aggressive cancer.
Peer reviewed publications:
Kim HR, Lin HM, Biliran H, Raz A. Cell Cycle Arrest and Inhibition of Anoikis by Galectin-3 in Human Breast Epithelial Cells. Cancer Res. 1999 59(16):4148-54.
McGowen R, Biliran H, Sager R, Sheng, S. The Surface of Prostate Carcinoma DU145 Cells Mediates the Inhibition of Urokinase-type Plasminogen Activator by Maspin. Cancer Res.2000 60(17):4771-8.
Biliran H, Sheng, S. Pleiotrophic Inhibition of Pericellular Urokinase-type Plasminogen Activator System by Endogenous Tumor Suppressive Maspin. Cancer Res. 2001 61(24):8676-82.
Sheng S, Biliran H., McGowen R. Maspin and Pericellular Plasminogen Activation in Cell-Matrix Interaction. 2001 In Maspin, Ed., Mary J. C. Hendrix, Landes Bioscience Medical Handbook Publisher, Georgetown, Texas.
Cher ML, Biliran HR Jr, Bhagat S, Meng Y, Che M, Lockett J, Abrams J, Fridman R, Zachareas M, Sheng S. Maspin Expression Inhibits Osteolysis, Tumor Growth, and Angiogenesis in a Model of Prostate Cancer Bone Metastasis. Proc Natl Acad Sci USA. 2003 100(13):7847-52.
Laakkonen P, Akerman ME, Biliran H, Yang M, Ferrer F, Karpanen T, Hoffman RM, Ruoslahti E. Antitumor Activity of a Homing Peptide that Targets Tumor Lymphatics and Tumor Cells. Proc Natl Acad Sci USA. 2004 101(25):9381-6.
Biliran H Jr, Wang Y, Banerjee S, Xu H, Heng H, Thakur A, Bollig A, Sarkar FH, Liao JD. Overexpression of Cyclin D1 Promotes Tumor Cell Growth and Confers Resistance to Cisplatin-Mediated Apoptosis in an Elastase-Myc Transgene-Expressing Pancreatic Tumor Cell Line. Clin Cancer Res. 2005 11(16):6075-86.
Thakur A, Xu H, Wang Y, Bollig A, Biliran H, Liao JD. The Role Of X-Linked Genes in Breast Cancer. Breast Cancer Res Treat. 2005 93(2):135-43.
Yin S, Lockett J, Meng Y, Biliran H Jr, Blouse GE, Li X, Reddy N, Zhao Z, Lin X, Anagli J, Cher ML, Sheng S. Maspin Retards Cell Detachment Via a Novel Interaction with the Urokinase-Type Plasminogen Activator/Urokinase-Type Plasminogen Activator Receptor System. Cancer Res. 2006 66(8):4173-81.
Biliran H Jr, Wang Y, Banerjee S, Xu H, Heng H, Thakur A, Bollig A, Sarkar FH, Liao JD. Myc-Induced Chemosensitization is Mediated by Suppression of Cyclin D1 Expression and Nuclear Factor-Kappa B Activity in Pancreatic Cancer Cells. Clin Cancer Res. 2007 13(9):2811-21.
Wang Y, Thakur A, Sun Y, Wu J, Biliran H, Bollig A, Liao DJ. Synergistic Effect of Cyclin D1 and C-Myc Leads to More Aggressive and Invasive Mammary Tumors in Severe Combined Immunodeficient Mice. Cancer Res. 2007 67(8):3698-707.
Liao DJ, Thakur A, Wu J, Biliran H, Sarkar FH. Perspectives on c-Myc, Cyclin D1, and their interaction in cancer formation, progression, and response to chemotherapy. Crit Rev Oncog. 2007 Nov;13(2):93-158.
Kairouz-Wahbe, R., Biliran H., Luo, X., Khor, I., Wankell, M., Besch-Williford, C., Pascual, J.,Oshima, R., and Ruoslahti, E. Anoikis effector Bit1 negatively regulates Erk activity. Proc. Natl. Acad. Sci. USA. 2007 105, 1528-1532.
Thakur A, Sun Y, Bollig A, Wu J, Biliran H, Banerjee S, Sarkar FH, Liao DJ. Anti-invasive and antimetastatic activities of ribosomal protein S6 kinase 4 in breast cancer cells. Clin Cancer Res. 2008 Jul 15;14(14):4427-36.
Biliran H, Jan Y, Chen R, Pasquale EB, Ruoslahti E. Protein kinase D is a positive regulator of Bit1 apoptotic function. J Biol Chem. 2008 Oct 17;283(42):28029-37.