Studying metabolic stress signaling in renal cancer

描述(申请人提供)：肿瘤生长需要高能量和营养供应。因此，癌细胞通常承受各种类型的代谢压力。克服代谢压力是癌症发展的关键一步。然而，癌细胞如何运用代谢适应策略在新陈代谢压力下生存和生长还不是很清楚。我们的长期目标是在癌症发展的背景下研究代谢应激反应中的关键信号通路，以便使医学界能够在治疗人类癌症时合理地针对这些通路。本研究的目的是研究FoxO转录因子在肾癌能量应激反应和肿瘤抑制中的作用。我们大量的初步数据支持我们提出的中心假设，即FoxO-BNIP3轴在抑制细胞生长(细胞体积增大)和细胞生存方面具有双重作用，以应对能量应激，而Foxos或BNIP3的丢失是肾癌细胞在肿瘤发展过程中适应能量应激的重要策略之一。这项研究的基本原理是，研究FoxO信号在能量应激反应和肾肿瘤抑制中的作用将促进我们对肾癌细胞如何绕过能量应激生存和生长的理解，并将为开发针对肾癌治疗中代谢应激的新的治疗策略或预后标志物提供重要的见解。为了验证我们的假设，我们将追求以下特定目标：特定目标1.确定FoxO信号在肾癌细胞能量应激反应中的调控和机制。具体目的2.确定Foxos和BNIP3在体内对mTORC1的抑制作用和对肾脏肿瘤的抑制作用。在预期结果方面，我们的研究将确定能量应激途径的新机制，阐明FoxO和BNIP3在肾癌中的抑瘤作用，并为FoxO/BNIP3表达在肾癌患者预后分层中的应用提供重要的见解。我们的建议具有很高的创新性，因为它集中在一条以前未探索过的途径上，填补了目前将能量应激与肾肿瘤发生联系起来的空白。我们提出的研究将对理解能量应激信号的基本机制和在临床上操纵人类癌症患者的分层和治疗能量应激途径具有重要影响。

DESCRIPTION (provided by applicant): 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.