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Targeting Calcium Channels to prevent EMT
Author(s) -
Hermanson Kole J,
Bhattacharya Atrayee,
Dhasarathy Archana J
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.647.11
Subject(s) - snail , biology , transcription factor , epithelial–mesenchymal transition , cancer research , cell migration , metastasis , downregulation and upregulation , microbiology and biotechnology , cancer cell , breast cancer , cell , cancer , gene , genetics , ecology
Breast cancer is the most common cancer among women worldwide, with many breast cancer‐associated deaths being attributed to metastasis of the primary tumor. In a process known as Epithelial to Mesenchymal transition (EMT), normal epithelial cells lose their cell‐to‐cell adhesions, become elongated and migratory, resulting in the mesenchymal phenotype. The SNAIL protein is known to be a master regulator of EMT, serving to repress expression of genes associated with cellular adhesion and activate genes involved in chemoresistance. In vivo and in vitro studies have both indicated that high levels of SNAIL correlate with poor prognosis, increased chemoresistance, and greater probability of recurrence of the tumor. Calcium signaling in the cell is important for several biological functions, and was implicated in EMT and breast cancer. To determine which calcium channels were involved in SNAIL upregulation during TGF‐β induced EMT, we blocked store‐operated calcium entry (SOCE) with 2‐aminoethoxydiphenylborane (2APB). This reduced cell migration but, paradoxically, increased the level of TGF‐β dependent SNAIL gene activation. We determined that this increased SNAIL transcription involved signaling through the AKT pathway and subsequent binding of NF‐κB (p65) at the SNAIL promoter in response to TGF‐β. We also demonstrated that the calcium channel protein ORAI3 and the stromal interaction molecule 1 (STIM1) are required for TGF‐β dependent SNAIL transcription. These results suggest that calcium channels differentially regulate cell migration and SNAIL transcription, indicating that each of these steps could be targeted to ensure complete blockade of cancer progression. We are currently testing whether this increase in SNAIL contributes to chemoresistance, and if blockade of ORAI3 can inhibit chemoresistance. Support or Funding Information This work was funded by grant support from the National Institutes of Health grants P20‐GM104360 to Archana Dhasarathy and UND School of Medicine and Health Sciences. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .