Life Sciences & Biotechnology
Title : | Characterization of novel molecular regulators of anoikis resistance in breast cancer: Molecular mechanisms and clinical significance |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Bramanandam Manavathi, University Of Hyderabad, Telangana |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | manavathibsl@uohyd.ac.in |
Equipments : | Fluorescence Microscopy |
Details
Executive Summary : | While extracellular matrix (ECM) is essential for the survival and proliferation of normal epithelial cells, loss of attachment by epithelial cells from ECM triggers detachment-induced cell death, a process called anoikis (in Greek, homelessness). Notwithstanding cancer cells display significant resistance to anoikis conferring metastasis. Mounting evidence points to autophagy, a cellular suicidal process triggered under stress, as a protector of cancer cells during tumorigenesis. Additionally, autophagy can induce migratory behavior in tumor cells by promoting anoikis resistance and dormancy. However, the molecular regulators and the signaling pathways that are intricately intertwined in autophagy-mediated anoikis resistance and metastasis remain elusive. HPIP is a stress response gene that is induced under hypoxia or energy stress (Penugurti et al., 2021; Khumukcham et al., 2022). Our preliminary data revealed its induced expression in response to the loss of extracellular matrix (ECM), indicating its possible role in anoikis resistance. Further, we also observed the interaction of HPIP with early endosomal protein Rab5, a GTPase, which was recently implicated in autophagosome production to regulate autophagy. Akin to HPIP, dysregulated expression of Rab5 is found in various cancers including breast cancer. This raises the tantalizing possibility that the HPIP-Rab5 complex may regulate anoikis resistance by controlling autophagy. The twist in the tale in this pathway is a plausible role for RNF126, which we identified as a novel interacting partner of Rab5 in a yeast genetic screen (Y2H). Because RNF126 is an E3 Ub ligase, whether RNF126 antagonizes anoikis resistance by regulating Rab5 levels via ubiquitination mediated proteolysis is an interesting aspect to be assiduously pursued. Together, this proposal envisages characterizing a novel signaling mechanism encompassing HPIP, Rab5, and RNF126 in control of anoikis resistance and tumor metastasis by in vitro and in vivo approaches. And yet, the analysis of their correlative expression in clinical breast tumors will predict the prognostic significance. |
Total Budget (INR): | 76,31,580 |
Organizations involved