Abstract
Potential tumor suppressor p42, ErbB3-binding protein 1 (EBP1) inhibits phosphoinositide 3-kinase (PI3K) activity reducing the p85 regulatory subunit. In this study, we demonstrated that overexpression of p42 promoted not only a reduction of wild type of p85 subunit but also oncogenic mutant forms of p85 which were identified in human cancers. Moreover, we identified the small fragment of C-terminal domain of p42 is sufficient to exhibit tumor suppressing activity of p42-WT, revealing that this small fragment (280–394) of p42 is required for the binding of both HSP70 and CHIP for a degradation of p85. Furthermore, we showed the small fragment of p42 markedly inhibited the tumor growth in mouse xenograft models of brain and breast cancer, resembling tumor suppressing activity of p42. Through identification of the smallest fragment of p42 that is responsible for its tumor suppressor activity, our findings represent a novel approach for targeted therapy of cancers that overexpress PI3K.
Highlights
With p85-specific primers. (d) GFP- mock vector or GFP-p42 (1 and 3 μg) was transfected into MDA-MB231 cells, following exposure to 10 μM of MG132 for 8 hours
As we have previously demonstrated that p42 acts tumor suppressor leading to a dramatic reduction in protein levels of the p85 subunit of phosphoinositide 3-kinase (PI3K) in glioblastoma cells and non-small cell lung cancer cells (NSCLC)[12,14], we wondered whether tumor suppressing effects of p42 inducing degradation of p85 is a general event in other types of cancer
The key finding of this report is that in glioma cells and certain types of breast cancer cells, overexpression of p42 permits access of HSP70/CHIP in the vicinity of p85 facilitating its proteasomal degradation, as evidenced by the observation that cells expressing p42 displayed a much lower intensity of p85 fluorescence compared with vector or p48-expressing cells
Summary
With p85-specific primers. (d) GFP- mock vector or GFP-p42 (1 and 3 μg) was transfected into MDA-MB231 cells, following exposure to 10 μM of MG132 for 8 hours. **p < 0.005 vs control, ##p < 0.005 vs indicated (e) MCF7 (left) and MDA-MB231 (right) cells were transfected (2 × 103 cells per 12 well plate) with total 4 μg of DNA constructs of any combinations. We proposed p42 as an inhibitor of phosphoinositide 3-kinase (PI3K), a well-known oncogene in various human cancers, through degradation of the p85 regulatory domain of PI3K, and demonstrated that p42 dramatically reduced p85 protein levels by linking p85 to proteasomal degradation mediated by the HSP70/CHIP E3 ligase complex[12] These findings suggest that the shorter isoform of p42 Ebp[1] acts as a potential tumor suppressor in various human cancers. We describe the minimal functional unit of p42 that efficiently inhibits PI3K through reduction of the p85 subunit and abrogates cancerous growth of tumor cells both in vitro and in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
