Life Sciences & Biotechnology
Title : | Role of mitochondrial localized NOTCH in metabolic reprogramming during reverse electron transport in cancer stem cells |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Rani U Ojha, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh |
Timeline Start Year : | 2022 |
Timeline End Year : | 2024 |
Contact info : | rani.ojha86@gmail.com |
Equipments : | Benchtop centrifuge |
Details
Executive Summary : | The mitochondrial electron transport chain is a site for oxidative phosphorylation and Reactive Oxygen (ROS), which are key sources of cancer development. Recent research has focused on identifying specific sites where ROS is generated and its effect on tumor formation, with reverse electron transport (RET) being a prime example. RET is produced when electrons from ubiquinol are transferred back to respiratory complex I, reducing NAD+ to NADH. Succinate, a key onco-metabolite, induces RET via the Complex-I by increasing the reduced ubiquinol pool. Reduced SDH activity and succinate accumulation have been associated with progressive disease or poor outcomes in endometrial cancer and hepatocellular carcinoma. The inter-relationship between succinate-driven NADH accumulation and its mechanism in cancer stem cell maintenance is also interesting. Notch-induced signaling cascades are key regulators of CSCs, with CD44 being a direct target of Notch. Notch inhibitors have been developed to treat cancer and its recurrence. Notch2 can regulate RET and RET-induced ROS formation by directly interacting with Complex-I. However, the detailed mechanism of RET-mediated ROS on Notch signaling downstream of the mitochondria remains largely unknown. The study will use Urogenital cancer, particularly bladder cancer, as a model. Bladder cancer stem cells are responsible for clinical characteristics, and NOTCH2 has been shown to act as an oncogene in bladder cancer, promoting cellular proliferation and metastasis. Understanding the role of CSCs in bladder cancer is critical for high recurrence and harnessing the Notch pathway and ETC inhibitors for therapeutic benefit in patients with Urogenital cancers. |
Co-PI: | Prof. Shrawan Kumar Singh, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh-160012 |
Total Budget (INR): | 27,77,500 |
Organizations involved