Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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(PQC1) PLK1 And EPHX3 Promotion Of Genomic Instability In Bronchial Dysplasia


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Bronchial dysplasia (BD) is a precancerous lesion that can progress to squamous cell carcinoma (SCC). Identification of lesions with high risk for progression is important to help identify cellular mechanisms underlying malignant transformation and to help identify patients that would benefit from preventive measures. We have compared high risk persistent BD to regressive BD by gene expression array analysis and identified more than 300 genes that are differentially expressed in persistent BD. Using a pathway analysis to identify genes with a strong relationship to persistence, we have identified two factors, polo-like kinase (PLK1) and epoxide hydrolase 3 (EPHX3), which demonstrate a synergistic relationship with persistence and suggest a potential interaction in promoting genomic instability in BD. EPHX3 converts cigarette smoke associated pro- carcinogenic polycyclic aromatic hydrocarbons (PAHs) to mutagenic metabolites. PLK1 promotes cell cycle progression through the G2-M checkpoint. This checkpoint normally operates to arrest the cell cycle when genetic damage is present with the subsequent induction of apoptosis in cells with extensive damage. We have hypothesized that the combination of increased mutational capacity coupled with G2-M checkpoint abrogation and subsequent cell cycle progression promotes and establishes genetic damage that mediates progression to invasive lung cancer. Furthermore, specific inhibitors of these factors are available suggesting a potential mechanism for preventing the development of lung SCC. We propose studies to establish the effect of PLK1 and EPHX3 inhibition on progression associated cellular activities and to assess the role of PLK1 and EPHX3 overexpression in promoting genomic instability using bronchial cell cultures established from persistent BD and normal bronchial epithelium. The first aim of the proposal will expand on preliminary studies that indicate PLK1 inhibition with Volasertib (Boehringer-Ingelheim) significantly reduces proliferation and induces apoptotic activity in cultured persisten BD derived epithelial cells without affecting these properties in normal epithelial cultures. Similarly, we have shown that the EPHX3 inhibitor, AUDA, reduces EPHX3 activity in SCC cell lines and will study its effects in BD derived cultures. The second aim will evaluate the role of genomic instability in persistent BD by characterizing the types of alterations and quantifying the amount of damage that are associated with carcinogen exposure. Genetic instability induced by tobacco smoke condensate treatment of persistent BD and normal bronchial cultures will be measured by genome-wide sequencing and methylation array analyses of cell lines cultured in the presence and absence of PLK1 and EPHX inhibitors to test our hypothesis. Long term goals that would be facilitated by the demonstration of PLK1 and EPHX3 dependent genomic instability include the establishment of an important cellular mechanism through which progression associated activities are mediated and the provision of rationale for the development of potentially effective chemopreventive therapy targeting these enzymes.
Collapse sponsor award id
R21CA190124

Collapse Time 
Collapse start date
2014-09-16
Collapse end date
2018-08-31

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