Year: 2015
Type: conference-abstract
Abstract: Chemo-resistance remains a major challenge in effective cancer treatment. Many mechanisms contribute to drug resistance. Results from experiments using cisplatin-resistant (CDDP) cancer cell lines suggest that malfunctioning of proteasome plays a role in resistance to platinum-based drugs. β5, a subunit of proteasome complex, was markedly reduced in CDDP cells, which is associated with increased p62 protein expression. p62 binds and aggregates intracellular accumulated polyubiquitinated proteins into aggresomes and prevents cell death. We hypothesize malfunctioning of the proteasome in cancer cells is associated with p62-mediated aggresomes contributing to chemo-resistance. To our knowledge, there is no prior data in the literature suggesting that proteasome could contribute to cancer drug resistance. 49 primary and metastatic lung and breast carcinoma tissue blocks were retrieved from archive. Tissue sections were stained for p62 expression using commercial antibody. Positivity for p62-mediated aggresomes was determined by the presence of coarse cytoplasmic granules. Chemotherapy history was obtained through chart review. The cancer study includes primary (n = 13) and metastatic (n = 13) lung adenocarcinoma; primary (n = 6) and metastatic (n = 3) lung squamous cell carcinoma (n = 6); metastatic lung small cell carcinoma (n = 4) and poorly differentiated carcinoma (n = 4); and metastatic breast carcinoma (n = 6). 57% of the cancers from patients with chemo-history contain p62-mediated aggresomes. In contrast, only 5% of the tumors in patients without chemo-history have p62-mediated aggresomes. Significantly (P = .002) higher percentage of chemo-experienced carcinoma shows p62-mediated aggresome formation compared to chemo-naïve carcinoma. These findings suggest that chemo-agents induce p62-mediated aggresome formation in carcinoma, which may cause proteasome malfunction and subsequent development of chemo-resistance. Analysis of β5 expression in these carcinomas is in progress.
Institution: University of Oklahoma Health Sciences Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2563466794