Shengkan (Victor) Jin  Associate Professor UMDNJ Department of Pharmacology Room 529 683 Hoes Lane West Piscataway. NJ 08854 (732) 235-4329/6197 FAX - 235-4073 jinsh@umdnj.edu

Autophagy in cancer biology, cancer therapy, and aging control

Humans, as well as other mammals with long life spans, face a formidable challenge: the accumulation of somatic mutations over time. These mutations often manifest themselves in various diseases, which eventually lead to the demise of the individual organism. Cancer is one of these diseases, which is caused by a combination of somatic genetic changes in a single cell that together result in uncontrolled cell growth and proliferation. In essence, cancer is an aging disease. It is not surprising that age is the single most important risk factor of cancer and many cellular processes are involved in both aging control and tumor suppression. The laboratory is focused on autophagy, an incredible new cellular process that we and others have demonstrated to play a critical role in preventing both cancer development and aging.

Autophagy is a higly regulated membrane-trafficking process leading to the lysosomal degradation (as shown in the inserted figure). During autophagy, cytoplasmic components are first sequestered in double-membrane vesicles--the autophagic vacuoles or autophagosomes. These vesicles then dock and fuse to lysosomes, where they are further degraded. It is believed that autophagic degradation plays a critical role for clearing damaged organelles and protein aggregates and is essential for the maintenance of a health cell.

The genes involved in autophagy, known as the autophagy-related genes (Atg), have been identified and characterized. The first autophagy gene in humans identified was named Beclin 1. Interestingly, Knocking out Beclin1 gene in mice increases cancer rates. Similarly, in humans Beclin 1 is monoallelically deleted in up to 40% of prostate cancers, 50% of breast cancers, and 75% of ovarian cancers. Part of the laboratory is working on the mechanism by which autophagy defect causes cancer. In addition, the lab is also working on pharmacologically manipulating autophagy in normal and cancer cells for tumor prevention and tumor therapy.

Autophagy is also involved in aging control. Inactivation of the beclin1 gene or other autophagy genes in C. elegans would reduce the life-spans of the worms. Apparently mitochondria, the organelles that are the major sources of intracellular reactive oxygen species (ROS) and are known to be a major contributor to aging, can only be degraded through autophagy. Part of the lab is working on how autophagy specifically degrades damaged mitochondria and how that would impact aging.

Selected Publications

Baerga R, Zhang Y, Chen PH, Goldman S, Jin S. (2009) Targeted deletion of autophagy-related 5 (atg5) impairs adipogenesis in a cellular model and in mice. Autophagy. Nov 2;5(8). [Epub ahead of print]

Pachikara N, Zhang H, Pan Z, Jin S, Fan H. (2009) Productive Chlamydia trachomatis lymphogranuloma venereum 434 infection in cells with augmented or inactivated autophagic activities. FEMS Microbiol Lett. 292(2):240-9.

Jin S, White E. (2008) Tumor suppression by autophagy through the management of metabolic stress. Autophagy. 4(5).

Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, White E. (2007) Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 21(13):1621-35.

Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, Chen G, Jin S, White E. (2007) Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. Jun 1;21(11):1367-81. Epub 2007 May 17. Erratum in: Genes Dev. 2007 Jul 1;21(13):1701.

Feng Z, Hu W, de Stanchina E, Teresky AK, Jin S, Lowe S, Levine AJ. (2007) The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res. 67(7):3043-53.

Zhang Y, Qi H, Taylor R, Xu W, Liu LF, Jin S. (2007) The role of autophagy in mitochondria maintenance: Characterization of mitochondrial functions in autophagy-deficient S. cerevisiae strains. Autophagy. 9:3(4)

Shengkan J* and White, E. (2007) Role of autophagy in cancer: Management of metabolic stress. Autophagy 3 (1):28-31 (* SJ is a Co- corresponding author)

Jin S, Dipaola RS, Mathew R, White E. (2007). Metabolic catastrophe as a means to cancer cell death. J Cell Sci.120:379-83.

Feng Z, Hu W, de Stanchina E, Teresky AK, Jin S, Lowe S, Levine AJ. (2007) The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res. 67(7):3043-53.

Hars, ES, Qi, H, Jin, S, Cai, L, Hu, C and Liu, L. (2007). Autophagy regulates ageing in C. elegans. Autophagy. 3(2):93-5.

Jin, S. (2006) Autophagy, mitochondria quality control, and oncogenesis. Autophagy. 2(2): 80-84.

Degenhardt, K., Mathew, R., Beaudoin, B., Bray, K., Anderson, D, Chen, G., Mukherjee, C., Shi, Y., Nelson, D.A., Jin, S., and White, E. (2006). Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 10(1):51-64.

Hait WN. Jin S. Yang JM. (2006) A matter of life or death (or both): understanding autophagy in cancer. Clin Cancer Res. 12(7 Pt 1):1961-5.

Wu H. Yang JM. Jin S. Zhang H. Hait WN. (2006) Elongation factor-2 kinase regulates autophagy in human glioblastoma cells. Cancer Res. 66(6):3015-23.

Levine AJ. Feng Z. Mak TW. You H. Jin S. (2006) Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev. 20(3):267-75.

Jin. S. (2005) p53. autophagy. and tumor suppression. Autophagy. 1 (3). 34-36.

Feng Z. Zhang H. Levine AJ. Jin S. (2005) The coordinate regulation of the p53 and mTOR pathways in cells.Proc Natl Acad Sci. 102(23):8204-9.

Yue. Z. Jin. S. Yang. C. Levine. AJ. Heintz. N. (2003). Beclin1. an autophagy gene essential for early embryo development. is a tumor suppressor. Proc. Nat. Acad. Sci. 100 (25): 15077-15082.

Jin. S. Kalkum. M. Overholtzer. M. Stoffel. A. Chait. BT and Levine. AJ (2003) CIAP1 and the serine protease HTRA2 are involved in a novel p53-dependent apoptotic Pathway in mammals. Genes and Development 17:359-367.