Rosen, Kirill V. - Dalhousie University - Department of Biochemistry & Molecular Biology

研究领域

Resistance to apoptosis induced by the loss of cell-extracellular matrix adhesion (anoikis) as a major prerequisite for cancer progression Detachment of many types of normal epithelial cells from the extracellular matrix (ECM) results in their programmed cell death, or apoptosis. This phenomenon is often referred to as anoikis, which means homelessness in Greek. Conversely, carcinomas, cancers derived from epithelial cells, grow in vivo as three-dimensional multicellular masses in which cells are deprived of proper contacts with the ECM but remain viable. Resistance to anoikis is now thought to be a major prerequisite for carcinoma growth, invasion and metastases, and may, therefore, represent a tumor-specific therapeutic target. However, no effort to exploit this property of malignant cells in the design of anti-cancer treatment has so far been made. Mechanistic studies that would lay a foundation for this novel approach represent the subject of our work. Molecular mechanisms of anoikis in normal epithelial cells One direction of our studies is aimed at understanding molecular mechanisms of anoikis in normal epithelial cells. Detachment-induced programmed cell death is thought to occur due to disengagement of specialized integrin receptors that are normally responsible for cell-ECM adhesion. Another cause of anoikis is detachment-triggered rearrangement of actin cytoskeleton. Programmed cell death is directly controlled by dozens of various proteins. We study how signaling events induced by cell detachment alter the expression and pro-anoikis activity of some of these regulators of apoptosis such as members of Bcl-2 family of proteins, caspases and their inhibitors (IAPs). Molecular mechanisms of resistance to anoikis in cancer cells It is now thought that oncogenes cause cancer partly through the inhibition of some of the pro-apoptotic changes induced by the loss of cell-ECM adhesion. Therefore, our other goal is to establish the mechanisms through which such major oncoproteins as Ras and epidermal growth factor receptor inhibit anoikis of cancer cells.

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Yoo BH, Khan IA, Koomson A, Gowda P, Sasazuki T, Shirasawa S, Gujar S, Rosen KV, (2017) Oncogenic RAS-induced downregulation of ATG12 is required for survival of malignant intestinal epithelial cells. Autophagy IN PRESS: Klionsky D.J., ….Rosen K.V…et al. (multiple authors), (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3d edition). Autophagy 12(1):1-222 [PubMed] Khan IA, Yoo BH, Masson O, Corkery D, Dellaire G, Baron S, Attardi LD and Rosen KV, (2016) ErbB2-dependent downregulation of a pro-apoptotic protein Perp is required for oncogenic transformation of breast epithelial cells. Oncogene 35:5759-57 [PubMed] Yoo BH, Masson O, Li Y, Khan I, Gowda P and Rosen KV, (2015) Anoikis of colon carcinoma cells triggered by β-catenin loss can be enhanced by Tumor Necrosis Factor Receptor 1 antagonists. Oncogene 34(38):4939-51 [PubMed] Yoo BH, Zagryazhskaya A, Li Y, Koomson A, Khan IA, Sasazuki T, Shirasawa S, and Rosen KV, (2015) Upregulation of ATG3 contributes to autophagy induced by the detachment of intestinal epithelial cells from the extracellular matrix, but promotes autophagy-independent apoptosis of the attached cells. Autophagy 11(8):1230-46 [PubMed] Arsenault DJ, Yoo BH, Rosen KV, Ridgway ND, (2013) ras-Induced up-regulation of CTP:phosphocholine cytidylyltransferase α contributes to malignant transformation of intestinal epithelial cells. J. Biol. Chem. 288:633-43 [PubMed] Junkins RD, Shen A, Rosen K, McCormick C, Lin TJ, (2013) Autophagy Enhances Bacterial Clearance during P. aeruginosa Lung Infection PLoS One 8(8): [PubMed] Yoo B, Berezkin A, Wang Y, Zagryazhskaya A and Rosen KV, (2012) Tumor suppressor protein kinase Chk2 is a mediator of anoikis of intestinal epithelial cells Int J Cancer 131:357-66 [PubMed] Klionsky DJ, ...Rosen KV,... (multiple authors), (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8:445-544 [PubMed] Yoo B.H., Wang Y, Erdogan M, Sasazuki S, Shirasawa S , Corcos L., Sabapathy K. and Rosen K.V. , (2011) Oncogenic ras-induced downregulation of a pro-apoptotic protease caspase-2 is required for malignant transformation of intestinal epithelial cells. J Biol Chem 286:38894-903 [PubMed] Yoo B.H., Wu X., Li Y., Haniff M., Sasazuki T., Shirasawa S., Eskelinen E.-L. and Rosen K.V., (2010) Oncogenic ras-induced downregulation of autophagy mediator Beclin-1 is required for malignant transformation of intestinal epithelial cells. J. Biol. Chem. 285:5438-49 [PubMed] Li H., Ray G., Yoo B.H., Erdogan M. and Rosen K.V. , (2009) Downregulation of DAP kinase-2 is required for beta-catenin-induced anoikis resistance of malignant epithelial cells. J. Biol. Chem. 284:2012-2022 [PubMed] Yoo B.H., Wu X., Derouet M., Haniff M., Eskelinen E.-L. and Rosen K.V., (2009) Hypoxia-induced downregulation of autophagy mediator Beclin-1 reduces the susceptibility of malignant intestinal epithelial cells to hypoxia-dependent apoptosis. Autophagy 5:1166-79 [PubMed] Derouet M., Wu X., May L., Yoo BH, Sasazuki T., Shirasawa S., Rak J. and Rosen KV, (2007) Acquisition of anoikis resistance promotes the emergence of oncogenic K-ras mutations in colorectal cancer cells and stimulates their tumorigenicity in vivo. Neoplasia 9(7):536-545 [PubMed] Liu, Z., Li, H., Derouet, M., Berezkin, A., Sasazuki, T., Shirasawa, S., and Rosen, K. , (2006) Oncogenic Ras inhibits anoikis of intestinal epithelial cells by preventing the release of a mitochondrial pro-apoptotic protein Omi/HtrA2 into the cytoplasm. J. Biol. Chem. 281:14738-47 [PubMed] Liu, Z., Li, H., Wu, X., Yoo, B., Yan, S., Stadnyk, A., Sasazuki, T., Shirasawa, S., LaCasse, E., Korneluk, RG. and Rosen KV, (2006) Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells. Oncogene 25:7680-90 [PubMed] Liu Z, Li H, Derouet M, Filmus J, LaCasse EC, Korneluk RG, Kerbel RS, and Rosen KV , (2005) ras oncogene triggers upregulation of cIAP2 and XIAP in intestinal epithelial cells: EGF receptor-dependent and -independent mechanisms of ras-induced transformation. J. Biol. Chem. 280:37383-37392 [PubMed] Yan SR, Joseph RR, Rosen K, Reginato MJ, Jackson A, Allaire N, Brugge JS, Jobin C, Stadnyk AW, (2005) Activation of NF-kappaB following detachment delays apoptosis in intestinal epithelial cells. Oncogene 24:6482-91 [PubMed]