Abstract 2782: The effect of ERRFI1 as a novel AKT regulator on cell proliferation and response to therapy is cell context dependent

Abstract

ERRFI1, a negative regulator of the EGFR family, is known to inhibit EGFR activation along with downstream of EGFR signaling. It is recognized as a tumor suppressor. However, ERRFI1 has multiple functions, and here, we present a novel function of ERRFI1. We found that it can directly interact with AKT and positively regulate AKT activity through regulation of AKT473 site by inhibiting PHLPP, the phosphatase access to AKT. The effect of this regulation on cell proliferation and on response to chemotherapy is cell context dependent, e.g. EGFR levels. We hypothesize that in cancer cells with high EGFR expression, down regulation of ERRFI1 enhances EGFR signaling, while on the other hand, increases AKT dephosphorylation. The strength of these two opposing signals will determine the eventual cellular phenotypes. In cancer cells with low EGFR expression, the direct effect of ERRFI1 on AKT is dominant, resulting in activation of AKT. To test these hypotheses, we knockdown ERRFI1 in multiple human cancer cell lines with different EGFR levels. Knockdown of ERRFI1 in high EGFR expressing cells resulted in an increase of cell proliferation and resistance to gemcitabine treatment, and this effect was due to the dominant negative effect of ERRFI1on EGFR, which was confirmed by increased EGFR signaling. Knockdown of ERRFI1 in cell lines with moderate level of EGFR also increased cell proliferation and resistance to gemcitabine, although biochemically, down regulation of ERRFI1 reduced AKT pS473 levels, but increased ERK/MAPK signaling. The addition of EGFR inhibitor, gefitinib, overcame gemcitabine resistance due to downregualtion of ERRFI1. In contrary, in cell lines with low level of EGFR, ERRFI1 positively regulated AKT signaling via directly binding to AKT and blocking PHLPP access to AKT. Therefore, down-regulation of ERRFI1 inhibited cell proliferation and sensitized cells to gemcitabine. In summary, we identified a novel function of ERRFI1 as a positive AKT regulator and its effect on cell proliferation and response to therapy is cell context dependent, e.g. EGFR levels. These results provide us insights into the dual roles of ERRFI1 in regulation of EGFR and AKT pathway and would help us to better individualize cancer therapy. Citation Format: Junmei Hou, Kaustubh N. Bhinge, Liewei Wang. The effect of ERRFI1 as a novel AKT regulator on cell proliferation and response to therapy is cell context dependent. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2782. doi:10.1158/1538-7445.AM2014-2782

Pathway-Based Analysis of Genome-Wide Association Data Identified SNPs in HMMR as Biomarker for Chemotherapy- Induced Neutropenia in Breast Cancer Patients

“…(3) The PAM50 genes which have been shown to be effective in predicting disease prognosis ( Nielsen et al, 2010 ) were also included. (4) Finally, genes studied in our laboratory shown to be functionally relevant in the AKT/mTOR signaling pathways in chemotherapy response ( Pei et al, 2009 ; Hou et al, 2014 ; Yu et al, 2017 ) and toxicity ( Ingle et al, 2010 ) were also added to the analysis.…”