Abstract
Epidemiologic evidence shows that obesity is associated with a greater risk of aggressive prostate cancer (PCa) and PCa-specific mortality and this is observed mainly in men with the TMPRSS2-ERG gene fusion. Obesity is often associated with comorbid conditions such as type 2 diabetes and hyperglycemia: we investigated whether some of the exposures associated with disturbed metabolism can also affect the frequency of this gene fusion. Fusion was induced in LNCaP PCa cells in normal or high levels of glucose, with or without insulin-like growth factor binding protein-2 (IGFBP-2) silenced or the presence of insulin-like growth factor-1 (IGF-I), insulin, or epidermal growth factor (EGF). RNA was extracted for analysis by nested PCR. Abundance of IGFBP-2, γH2AX, DNA-dependent protein kinase catalytic subunit (DNAPKcs), and β-actin were analyzed by Western immunoblotting. Our data suggest that hyperglycemia-induced IGFBP-2 increased the frequency of the gene fusion that was accompanied by decreased levels of DNAPKcs implying that they were mediated by alterations in the rate of repair of double-strand breaks. In contrast insulin, IGF-I and EGF all decreased gene fusion events. These novel observations may represent a further mechanism by which obesity can exert an effect aggravating PCa progression.
Highlights
The TMPRSS2-ERG fusion oncogene is thought to be important during tumor progression and development as it is found in approximately half of all prostate cancer (PCa) biopsies and in metastases [1,2,3].Joining of the 5′-untranslated region of TMPRSS2 with the oncogenic ETS transcription factor, ERG culminates in the TMPRSS2-ERG gene fusion
We have shown previously that hyperglycemia-induced chemoresistance in PCa cells and that this was mediated by an epigenetic upregulation of insulin-like growth factor binding protein-2 (IGFBP-2) [9]
We identified that IGFBP-2 inhibited PTEN function in PCa cells by increasing its phosphorylation [18] and global expression profiling indicated that IGFBP-2 was the most important biomarker to indicate the status of PTEN in tumors [19]
Summary
Epidemiologic evidence shows that obesity is associated with a greater risk of aggressive prostate cancer (PCa) and PCa-specific mortality and this is observed mainly in men with the TMPRSS2-ERG gene fusion. Obesity is often associated with comorbid conditions such as type 2 diabetes and hyperglycemia: we investigated whether some of the exposures associated with disturbed metabolism can affect the frequency of this gene fusion
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
