Cenexin and PLK1: A Sensor for Chromosome Misalignment
Abstract
Cell division is a process whereby genetic material is duplicated, separated, and packaged to yield two daughter cells. This process relies on spatial and temporal synchronization of protein kinase activity at the mitotic spindle, a macromolecular machine that segregates chromosomes toward the daughter cells. A major generator of this machine and organizer of mitotic signaling is the centrosome. Interphase cells have a single centrosome that nucleates microtubules for cellular material to transport on. When cells decide to divide into two, they duplicate their genetic material and their centrosomes to make two mitotic spindle poles, which function to nucleate microtubules to capture duplicated genetic material and distribute it equally to each daughter cell. In primary prostate cancer cells, we find that a large proportion of cells (~30%) contain supernumerary centrosomes (>3 centrosomes/cell). We also identified in these samples that contained supernumerary centrosomes elevated amounts of the mitotic kinase PLK1, which is known to regulate centrosome function, number, and mitotic progression. Thus, we propose a testable model that defects in centrosome number and function can lead to genomic instability causing a normal prostate epithelial cell genome to behave like a cancer genome. To test this, we will first identify the mechanism of centrosome amplification and subsequently determine its impact on genome stability using primary prostate cancer cells grown in a three-dimensional (3-D) culture. The advantage of 3-D culture systems is that, unlike commonly used monolayer cultures, 3-D cultures recapitulate many features of prostate acini in vivo providing a context in which to study the functional consequences of supernumerary centrosomes and cancer genes such as PLK1. Optimization of imaging strategies for 3-D cultures may eventually allow for high throughput screening of experimental therapeutics applied to ex vivo patient samples, with subsequent tailoring of treatments specific to that individual. These studies may also identify pharmacological strategies for targeted kinase inhibition inside the cell, which is at the frontier of precision medicine. Thus, our studies address two PCRCP overarching challenges where we will contribute to defining the biology of lethal prostate cancer development and provide treatment strategies for possible improved therapeutic outcomes. In conclusion, our studies will address the overall hypothesis that deregulation of centrosome based signaling events leads to genomic instability and subsequent metastasis in prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010585
Entities
People
- Heidi Hehnly
Organizations
- Syracuse University
- United States Army