Tumor growth requires high energy and nutrient supplies. As a result, cancer cells usually undergo various types of metabolic stress. Overcoming metabolic stress is a critical step in cancer development. However, how cancer cells engage strategies of metabolic adaptation to survive and grow under metabolic stress is not well understood. Our long-term goal is to study key signaling pathways in metabolic stress response in the context of cancer development, so as to enable the medical community to rationally target such pathways in the treatment of human cancers. The objective of this application is to study the roles of FoxO transcription factors (FoxOs) in energy stress response and tumor suppression in renal cell carcinoma (RCC). Our extensive preliminary data support the central hypothesis of our proposal that FoxO-BNIP3 axis plays a dual role in inhibiting both cell growth (cell size increase) and cell survival in response to energy stress, and loss of FoxOs or BNIP3 is one important strategy renal cancer cells adapt to energy stress during tumor development. The rationale for the proposed research is that studying the roles of FoxO signaling in energy stress response and renal tumor suppression will advance our understanding of how renal cancer cells bypass energy stress to survive and grow, and will provide important insights on the development of novel therapeutic strategies or prognostic markers targeting metabolic stress in renal cancer treatment. To test our hypothesis, we will pursue the following specific aims:
Specific Aim 1. To determine the regulation and mechanisms of FoxO signaling in energy stress response in renal cancer cells.
Specific Aim 2. To determine the roles of FoxOs and BNIP3 in mTORC1 inhibition and renal tumor suppression in vivo. With respect to expected outcomes, our proposed studies will identify novel mechanisms of energy stress pathways, clarify the tumor suppression function of FoxO and BNIP3 in renal cancer, and provide important insights on the use of FoxO/BNIP3 expression in prognostic stratification of renal cancer patients. Our proposal is highly innovative, because it focuses on a previously unexplored pathway that fills in the current gap to link energy stress to renal tumor development. Our proposed studies will have significant impact on both understanding the fundamental mechanisms of energy stress signaling and manipulating energy stress pathways clinically in the stratification and treatment of human cancer patients.
Overcoming metabolic stress is a critical step in cancer development. The objective of this application is to study the roles of FoxO signaling in energy stress response and tumor suppression in renal cancer. Our proposed studies will have significant impact on understanding the fundamental mechanisms of energy stress signaling and manipulating energy stress pathways clinically in the stratification and treatment of human cancer patients.
|Xiao, Zhen-Dong; Han, Leng; Lee, Hyemin et al. (2017) Energy stress-induced lncRNA FILNC1 represses c-Myc-mediated energy metabolism and inhibits renal tumor development. Nat Commun 8:783|
|Dai, Fangyan; Lee, Hyemin; Zhang, Yilei et al. (2017) BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response. Proc Natl Acad Sci U S A 114:3192-3197|
|Koppula, Pranavi; Zhang, Yilei; Shi, Jiejun et al. (2017) The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate. J Biol Chem 292:14240-14249|
|Kim, Jongchan; Siverly, Ashley N; Chen, Dahu et al. (2016) Ablation of miR-10b Suppresses Oncogene-Induced Mammary Tumorigenesis and Metastasis and Reactivates Tumor-Suppressive Pathways. Cancer Res 76:6424-6435|
|Lee, Hyemin; Dai, Fangyan; Zhuang, Li et al. (2016) BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21. Oncotarget 7:19134-46|
|Xiao, Zhen-Dong; Liu, Xiaowen; Zhuang, Li et al. (2016) NBR2: A former junk gene emerges as a key player in tumor suppression. Mol Cell Oncol 3:e1187322|
|Liu, Xiaowen; Xiao, Zhen-Dong; Han, Leng et al. (2016) LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress. Nat Cell Biol 18:431-42|
|Xiao, Zhen-Dong; Zhuang, Li; Gan, Boyi (2016) Long non-coding RNAs in cancer metabolism. Bioessays 38:991-6|
|Liu, Xiaowen; Gan, Boyi (2016) lncRNA NBR2 modulates cancer cell sensitivity to phenformin through GLUT1. Cell Cycle 15:3471-3481|
|Liu, Xiaowen; Xiao, Zhen-Dong; Gan, Boyi (2016) An lncRNA switch for AMPK activation. Cell Cycle 15:1948-9|
Showing the most recent 10 out of 13 publications