Acetyl isogambogic acid activates unfolded protein response and apoptosis in head and neck cancer

Mehrnoosh Ghafouri AbbasAbadi, Chester Gauss, Thomas Jetmore, Jordyn Lucas, Jared Lin, Sarah Colbert, Gauthom Baddigam, Syed Akbari, Michael U. Callaghan, Yue Xi and Andrew M. Fribley Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine. 421 E. Canfield Detroit, MI 48201

Squamous cell carcinoma is a cancer that arises from squamous cells. Head and neck squamous cell carcinoma (HNSCC) develop in the mucous membranes of the mouth, nose, and throat. HNSCC is the sixth most common malignancy in the world with 650,000 new diagnosis and 350,000 death every year. Currently chemotherapy and radiation are the mainstay treatments however, the 5 year survival rate for patients with stage 3 or 4 disease is still less than 50%. There is an urgent unmet clinical need to investigate and discover novel treatments for these patients. HNSCC is characterized by dysregulated cell growth rate and aberrant protein synthesis which leads to increase protein folding demand and the need for chaperones. This high protein demand leads to accumulation of misfolded proteins in endoplasmic reticulum that causes ER stress and results in Unfolded Protein Response (UPR).  To address the shortcoming of the current treatments for HNSCC, we attempted a high-throughput screen on a compound library of 2400 compounds in order to identify compounds that could induce ER stress and enforce a terminal (apoptotic) UPR in HNSCC. Acetyl-IsoGambogic Acid (AIGA) emerged  as a hit; AIGA strongly showed activation of UPR and apoptotic pathways. Cell proliferation assays, gene expression,  protein immunoblot profiles, DNA fragmentation assay, and fluorescence activated cell sorting (FACS)  were consistent with activation of UPR and apoptosis in a panel of HNSCC cell lines. Considered together these data confirmed that our HTS approach could successfully identify novel inducers of a terminal unfolded protein response. Natural compounds such as AIGA might be able to  provide a new therapeutic approach for treating patients with HNSCC. 

Additional Abstract Information

Presenter: Mehrnoosh Ghafouri AbbasAbadi

Institution: Wayne State University

Type: Oral

Subject: Biology

Status: Approved

Time and Location

Session: Oral 8
Date/Time: Tue 5:00pm-6:00pm
Session Number: 804
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