Borrelidin Induces the Unfolded Protein Response in Oral Cancer Cells and Chop-Dependent Apoptosis

作者：Sidhu Alpa; Miller Justin R; Tripathi Ashootosh; Garshott Danielle M; Brownell Amy L; Chiego Daniel J; Arevang Carl; Zeng Qinghua; Jackson Leah C; Bechler Shelby A; Callaghan Michael U; Yoo George H; Sethi Seema; Lin Ho Sheng; Callaghan Joseph H; Tamayo Castillo Giselle; Sherman David H^*; Kaufman Randal J; Fribley Andrew M

来源：ACS Medicinal Chemistry Letters, 2015, 6(11): 1122-1127.

DOI：10.1021/acsmedchemlett.5b00133

• UPR
• borrelidin
• Chop
• Xbp 1
• BiP/GRP78
• oral cancer
• natural products
• high throughput screen
• ER stress
• oral squamous cell carcinoma
• protein folding

Oral squamous cell carcinoma (OSCC) is the most common cancer affecting the oral cavity, and US clinics will register about 30,000 new patients in 2015. Current treatment modalities include chemotherapy, surgery, and radiotherapy, which often result in astonishing disfigurement. Cancers of the head and neck display enhanced levels of glucose-regulated proteins and translation initiation factors associated with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Previous work demonstrated that chemically enforced UPR could overwhelm these adaptive features and selectively kill malignant cells. The threonyl-tRNA synthetase (ThRS) inhibitor borrelidin and two congeners were discovered in a cell-based chemical genomic screen. Borrelidin increased XBPI splicing and led to accumulation of phosphorylated eIF2 alpha and UPR-associated genes, prior to death in panel of OSCC cells. Murine embryonic fibroblasts (MEFs) null for GCN2 and PERK were less able to accumulate UPR markers and were resistant to borrelidin. This study demonstrates that UPR induction is a feature of ThRS inhibition and adds to a growing body of literature suggesting ThRS inhibitors might selectively target cancer cells.

• 出版日期2015-11