Inhibition of Mitochondrial Fission and Its Effect on Pancreatic Cancer
Mentor 1
Blake Hill
Start Date
28-4-2023 12:00 AM
Description
Mitochondrial fission is the process by which mitochondria divide and is necessary for organelle segregation into daughter cells during cytokinesis. Excessive mitochondrial fission has been linked to increased tumor growth in many cancers, including pancreatic cancer. Pancreatic cancer is one of the deadliest cancers in the U.S. with a 5-year survival rate of about 10%. The goal of this project is to advance a novel therapeutic route against pancreatic cancer by targeting mitochondrial fission proteins. Inhibition of mitochondrial fission, either genetically or pharmacologically, blocks oncogenesis. Dynamin-related protein 1 (Drp1) is the mechanoenzyme that performs mitochondrial fission, and it is recruited to sites of fission by mitochondrial fission protein 1 (Fis1). By inhibiting Fis1, which is three times more upregulated in pancreatic cancer than Drp1, mitochondrial fission will be restricted. We have developed pep213, a novel peptide inhibitor, that inhibits Fis1 and prevents mitochondrial fission from occurring. However, pep213 was designed to block a version of Fis1 that lacks its transmembrane domain that anchors it to the outer mitochondrial membrane (Fis1ΔTM), and it has not been tested in vitro against the full-length Fis1. We presume that constituting Fis1 as it appears in its native state in vivo will influence the binding affinity of inhibitors. Therefore, we will test the hypothesis that inhibitors designed against Fis1ΔTM will have an enhanced affinity for membrane-anchored Fis1. Using microscale thermophoresis and nuclear magnetic resonance (NMR), we will measure binding affinities of pep213 and small molecules to full-length Fis1 and compare them to Fis1ΔTM. We will then test how inhibited Fis1 impacts pancreatic cancer cell proliferation by using cellular proliferation assays with normal pancreatic cancer cells and those which have genetically and pharmacologically inhibited Fis1. Understanding these mechanisms can provide the groundwork for further therapeutic research for this intractable cancer.
Inhibition of Mitochondrial Fission and Its Effect on Pancreatic Cancer
Mitochondrial fission is the process by which mitochondria divide and is necessary for organelle segregation into daughter cells during cytokinesis. Excessive mitochondrial fission has been linked to increased tumor growth in many cancers, including pancreatic cancer. Pancreatic cancer is one of the deadliest cancers in the U.S. with a 5-year survival rate of about 10%. The goal of this project is to advance a novel therapeutic route against pancreatic cancer by targeting mitochondrial fission proteins. Inhibition of mitochondrial fission, either genetically or pharmacologically, blocks oncogenesis. Dynamin-related protein 1 (Drp1) is the mechanoenzyme that performs mitochondrial fission, and it is recruited to sites of fission by mitochondrial fission protein 1 (Fis1). By inhibiting Fis1, which is three times more upregulated in pancreatic cancer than Drp1, mitochondrial fission will be restricted. We have developed pep213, a novel peptide inhibitor, that inhibits Fis1 and prevents mitochondrial fission from occurring. However, pep213 was designed to block a version of Fis1 that lacks its transmembrane domain that anchors it to the outer mitochondrial membrane (Fis1ΔTM), and it has not been tested in vitro against the full-length Fis1. We presume that constituting Fis1 as it appears in its native state in vivo will influence the binding affinity of inhibitors. Therefore, we will test the hypothesis that inhibitors designed against Fis1ΔTM will have an enhanced affinity for membrane-anchored Fis1. Using microscale thermophoresis and nuclear magnetic resonance (NMR), we will measure binding affinities of pep213 and small molecules to full-length Fis1 and compare them to Fis1ΔTM. We will then test how inhibited Fis1 impacts pancreatic cancer cell proliferation by using cellular proliferation assays with normal pancreatic cancer cells and those which have genetically and pharmacologically inhibited Fis1. Understanding these mechanisms can provide the groundwork for further therapeutic research for this intractable cancer.
