Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with multi-system manifestations including seizures, mental retardation, autism, and tumors in the brain, heart, skin, kidney, and lung. 80% of TSC patients develop renal angiomyolipomas; cysts and carcinomas also occur. TSC is caused by germline inactivating mutations in TSC1 or TSC2, which encode hamartin (TSC1) and tuberin (TSC2), respectively. TSC1 and TSC2 function as a complex to inhibit mammalian target of rapamycin (mTOR) complex 1 (mTORC1), and tumors from TSC patients show hyperactivation of mTORC1. mTORC1 is a key regulator of protein synthesis, cell growth and cellular metabolism. Treatment with rapamycin or everolimus, mTORC1 inhibitors, partially decreases the volume of renal angiomyolipomas and brain tumors in TSC, but tumors regrow when treatment is discontinued. The long-term benefits and hazards of rapamycin are uncertain. Our central hypothesis is that loss of TSC2 enhances the expression and activity of components in phospholipase A2-cyclooxygenases-prostaglanin receptors (PAL2-COX1/2-EP3) pathways, and thereby leads to enhanced production of prostaglandins and promotes TSC-related tumor development. The long-term goal of this proposal is to identify the molecular mechanisms and significance of TSC2-dependent and mTORC1-independent up-regulation of COX-2 and prostaglandin biosynthesis, and thereby facilitate the potential application of prostaglandins as biomarkers of disease severity, and the development of prostaglandin inhibitors as therapeutic approaches for tumors occurring in TSC, and tumors with TSC1/TSC2 involvement occurring in non-TSC patients.
This proposal will investigate the mechanism and effect of phospholipase A2 (PLA2), cyclooxygenses (COX-1 and COX-2), and prostaglandin receptor EP3 in TSC2-deficient patient angiomyolipoma-derived cells. Novel therapeutic and diagnostic prostaglandin-related targets in TSC disorders may be identified and lead to improve clinical care with combination treatment including rapamycin for TSC-related diseases. Furthermore, novel pathway regulating PLA2-COX-1/2-EP3 and prostaglandin biosynthesis will also be identified. A potential of using prostaglandins as plasma biomarkers of TSC will be determined.
|Lam, Hilaire C; Baglini, Christian V; Lope, Alicia Llorente et al. (2017) p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis. Cancer Res 77:3255-3267|
|Lee, Gina; Zheng, Yuxiang; Cho, Sungyun et al. (2017) Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling. Cell 171:1545-1558.e18|
|Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Goldberg, Alexander A; Joung, Kwang-Bo; Mansuri, Asma et al. (2016) Oncogenic effects of urotensin-II in cells lacking tuberous sclerosis complex-2. Oncotarget 7:61152-61165|
|Manna, Subrata; Bostner, Josefine; Sun, Yang et al. (2016) ERR? Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer. Clin Cancer Res 22:1421-31|
|Li, Jing; Shin, Sejeong; Sun, Yang et al. (2016) mTORC1-Driven Tumor Cells Are Highly Sensitive to Therapeutic Targeting by Antagonists of Oxidative Stress. Cancer Res 76:4816-27|
|Priolo, Carmen; Ricoult, Stéphane J H; Khabibullin, Damir et al. (2015) Tuberous sclerosis complex 2 loss increases lysophosphatidylcholine synthesis in lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 53:33-41|
|Li, Jing; Csibi, Alfredo; Yang, Sun et al. (2015) Synthetic lethality of combined glutaminase and Hsp90 inhibition in mTORC1-driven tumor cells. Proc Natl Acad Sci U S A 112:E21-9|
|Alayev, Anya; Salamon, Rachel S; Sun, Yang et al. (2015) Effects of combining rapamycin and resveratrol on apoptosis and growth of TSC2-deficient xenograft tumors. Am J Respir Cell Mol Biol 53:637-46|
|Sun, Yang; Gallacchi, Dana; Zhang, Erik Y et al. (2014) Rapamycin-resistant poly (ADP-ribose) polymerase-1 overexpression is a potential therapeutic target in lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 51:738-49|
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