UCHL1-PKM2 axis dysregulation is associated with promoted proliferation and invasiveness of urothelial bladder cancer cells

Abstract

Background: Bladder cancer is one of the most common type of cancers globally, and the majority of cases belong to urothelial bladder carcinoma (UBC) type. Current researches have demonstrated that multiple genomic abnormalities are related to the sensitivity of cisplatin-based chemotherapy in bladder cancer patients. Previous findings have indicated a controversial role of Ubiquitin Carboxy-Terminal Hydrolase L1 (UCHL1) in malignancy, so we aimed to further explore the role of UCHL1 in UBC. Methods: UBC cell lines and The Cancer Genome Atlas (TCGA) in-silico datasets were utilized to investigate UCHL1 expression pattern and functional as well as prognostic impacts in UBC cancer cell line models and patients. UCHL1 overexpression and silencing vectors and subsequent immunoprecipitation/ubiquitination experiments in combination of cellular functional assays were conducted to explore UCHL1-PKM2 interaction axis and its significance in UBC malignancy. Results: UCHL1 was significantly up-regulated in UBC cancer cells and UCHL1 high-expression was associated with higher pathology/clinical grade and significantly inferior overall prognosis of UBC patients. UCHL1 interacted with PKM2 and enhanced PKM2 protein level through inhibition of PKM2 protein degradation via ubiquitination process. UCHL1-PKM2 interaction significantly promoted UBC cellular proliferation, metastasis and invasion activities. Conclusion: UCHL1-PKM2 interaction played an interesting role in UBC tumor cell proliferation, migration and metastasis. Our study suggests PKM2-targeted treatment might have a potential value in metastatic malignancy therapy development in the future.

Nicotinamide riboside Induced Energy Stress and Metabolic Reprogramming in BEAS-2B Cells

“…In parallel, NR exposure led to decreased abundance of proteins involved in the folding, aggregation, or turnover of proteins, in l -serine biosynthesis, mRNA transcription, posttranscriptional gene silencing, double-strand break repair, and regulation of protein phosphorylation (Figures c, , S5 and Table S6). Among the 12 downregulated proteins described here, 11 have been shown to be upregulated in different types of cancer. − Downregulation of these proteins may have a role in slowing the growth and inducing apoptosis of the NR exposed cells, despite the shift to glycolytic metabolism. To the best of our knowledge, this is the first report showing the modulation of the abundance of the described sets of proteins by NR exposure.…”

“…Except for cellular tumor antigen p53 (TP53), the other 11 proteins have been shown to be upregulated in different types of cancer (Table S6). − Six of these proteins are involved in the folding, aggregation, or turnover of proteins [hypoxia up-regulated protein 1 (HYOU1), heat shock 70 kDa protein 1A or 1B (HSPA1A or 1B), protein disulfide-isomerase (P4HB), prolyl 4-hydroxylase subunit alpha-2 (P4HA2), serpin H1 (SERPINH1), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1)]. Two are involved in l -serine biosynthesis [phosphoserine aminotransferase (PSAT1), phosphoserine phosphatase (PSPH)].…”