Tuberous sclerosis complex (TSC) is a human syndrome characterized by widespread development of benign tumors in a variety of organs including skin, brain, lung, heart and kidney. TSC is caused by mutation in either the TSC1 or TSC2 gene. Recent studies have indicated that TSC1 and TSC2 suppress the mammalian target of rapamycin (mTOR) signaling pathway to control cell growth;thus, abnormal activation of mTOR signaling as a result of mutation in TSC1 or TSC2 gene may underlie the pathogenesis of TSC. While mechanisms associated with mTOR regulation and with mTOR downstream effects have been partly characterized, much is still unknown regarding these mechanisms. Importantly, treatment of TSC is palliative and no effective cure is known. We have recently found that the IKK complex (key upstream regulator of the transcription factor NF-kB) interacts with the mTOR complex and significantly increases both mTORC1 and mTORC2 activity. Additionally, our results revealed that mTOR controls IKK/NF-NF-kB activation reciprocally. These results implicate IKK/NF- kappaB pathway as a novel regulator of TSC/mTOR signaling pathway. My data also demonstrate that both TSC2 and rapamycin regulate IKK/NF-kB activity through mTORC1 in an Akt-dependent manner. Based on my published studies and preliminary data, I hypothesize that IKK and NF-kB are critical regulators and effectors for mTOR and Akt in controlling the progression of TSC, and that rapamycin in combination with an IKK inhibitor could effectively block the activity of mTOR, Akt and IKK/NF-:B and ultimately block progression of TSC in TSC animal models. I will characterize the mechanism whereby IKK? controls TORC1 and mTORC2 activity in several cancer cells and in TSC2 -/- MEF cells. I will extensively examine how TSC2 and rapamycin, in combination with an IKK inhibitor, affect NF-kB activity and TSC progression in cells and TSC animal models. The goal of this proposal is to achieve a mechanistic understanding of the interaction between IKK/NF-kB and mTOR pathways in promoting cell survival and growth, and progression of TSC. The proposed genetic and biochemical analyses and animal model studies will provide novel insight into the regulation and function of TSC/mTOR and IKK/NF-kB pathways, and the progression of TSC. Further studies could lead to the identification of new therapeutic targets and ultimately help develop rational, mechanism- based treatment strategies that target TSC and TSC-related tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA149178-04
Application #
8735087
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Spalholz, Barbara A
Project Start
2013-09-16
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Li, Zhipeng; Yang, Zejia; Passaniti, Antonino et al. (2016) A positive feedback loop involving EGFR/Akt/mTORC1 and IKK/NF-kB regulates head and neck squamous cell carcinoma proliferation. Oncotarget 7:31892-906
Dan, Han C; Antonia, Ricardo J; Baldwin, Albert S (2016) PI3K/Akt promotes feedforward mTORC2 activation through IKK?. Oncotarget 7:21064-75
Zhang, Yanting; Lapidus, Rena G; Liu, Peiyan et al. (2016) Targeting I?B Kinase ?/NF-?B Signaling in Human Prostate Cancer by a Novel I?B Kinase ? Inhibitor CmpdA. Mol Cancer Ther 15:1504-14
Li, Zhipeng; Yang, Zejia; Lapidus, Rena G et al. (2015) IKK phosphorylation of NF-?B at serine 536 contributes to acquired cisplatin resistance in head and neck squamous cell cancer. Am J Cancer Res 5:3098-110
Gao, Yu; Gartenhaus, Ronald B; Lapidus, Rena G et al. (2015) Differential IKK/NF-?B Activity Is Mediated by TSC2 through mTORC1 in PTEN-Null Prostate Cancer and Tuberous Sclerosis Complex Tumor Cells. Mol Cancer Res 13:1602-14
Dan, Han C; Ebbs, Aaron; Pasparakis, Manolis et al. (2014) Akt-dependent activation of mTORC1 complex involves phosphorylation of mTOR (mammalian target of rapamycin) by I?B kinase ? (IKK?). J Biol Chem 289:25227-40