Exploration of DJ-1 as a Therapeutic Target in Metastatic Melanoma

Williams, Megan Jane (2024) Exploration of DJ-1 as a Therapeutic Target in Metastatic Melanoma. Masters thesis, University of East Anglia.

PDF Restricted to Repository staff only until 30 April 2027. Request a copy

Abstract

DJ-1/PARK7 is an antioxidant defence protein commonly associated with Parkinson’s disease (PD). However, more recently upregulation of DJ-1/PARK7 has been linked to poor prognosis and outcomes in cancers such as lung, breast and some skin cancers. It is believed to increase aggressiveness and progression of cancer through increasing cancer cell survival and metastasis, as well as decreasing drug sensitivity. This study aimed to determine the expression of DJ-1/PARK7 in cancer, its role in melanoma and determine if it could be a potential therapeutic target in melanoma. DJ-1/PARK7 expression was found to be increased in several cancers, including melanoma, compared to normal matched patient tissue. Further validation in a range of human cancer cell lines showed a variation in expression across different cancer types, with the highest mRNA and protein expression found in SK-MEL-28 melanoma, THP-1 acute myeloid leukaemia and LnCaP prostate cancer cells. Variation in expression was also seen across different melanoma cell lines, with M308 and SK-MEL-28 cells having the highest expression. Knockdown of DJ-1/PARK7 in A375 melanoma cells, a highly metastatic cell line with relatively high expression of DJ-1/PARK7 mRNA and protein, resulted in decreased cell viability and an increase in caspase 3/7, suggesting DJ-1 may confer anti-apoptotic and increased proliferative effects on A375 cells. DJ-1/PARK7 expression has also previously been found to activate the oxidative stress response transcription factor Nrf2, upregulation of which has also been associated with poor outcomes in cancer patients. In this study, DJ-1/PARK7 expression correlated to Nrf2 expression. Of the cell lines investigated, those that expressed high levels of DJ-1/PARK7 (e.g. SK-MEL-28 and THP-1 cells) also had high expression of Nrf2. Additionally, the lowest expressing DJ-1/PARK7 cells similarly had lower expression of Nrf2 (e.g. H292 lung cancer cells). This study also aimed to investigate DJ-1/PARK7 as a potential therapeutic target in melanoma. STK793590 is a reported inhibitor of the DJ-1/PARK7 homodimer. STK793590 reduced cell viability of A375 and SK-MEL-28 cells and non-significantly reduced the migration of A375 cells at concentrations ≥20 μM. Novel peptides designed to target the DJ-1/PARK7 homodimer were also investigated: however, they had no significant effects on cell viability or migration. Further studies are required to determine cell uptake of these peptides. In conclusion, DJ-1/PARK7 expression is increased in melanoma and results in increased cellular proliferation and decreased cell death. As such, this study has identified that DJ-1/PARK7 could be a valid target in future chemotherapeutics for melanoma.

Item Type:	Thesis (Masters)
Faculty \ School:	Faculty of Science > School of Pharmacy (former - to 2024)
Depositing User:	Chris White
Date Deposited:	13 Nov 2024 11:24
Last Modified:	13 Nov 2024 11:24
URI:	https://ueaeprints.uea.ac.uk/id/eprint/97677
DOI:

Actions (login required)

View Item