Cantharidins Induce ER Stress and a Terminal Unfolded Protein Response in OSCC. (February 2015)

• Record Type: Journal Article
• Authors: Xi, Y.; Garshott, D.M.; Brownell, A.L.; Yoo, G.H.; Lin, H.-S.; Freeburg, T.L.; Yoo, N.G.; Kaufman, R.J.; Callaghan, M.U.; Fribley, A.M.
• Is Part Of: Journal of dental research. Volume 94:Number 2(2015:Feb.)
• Page Start: 320
• Page End: 329
• Publication Date: 2015-02
• Subjects: UPR -- CHOP -- ATF4 -- cantharide -- natural products -- chemotherapy; Dentistry -- Periodicals; Dentistry -- Social aspects -- Periodicals; Dentistry -- Periodicals; Research -- Periodicals; 617.6005
• DOI: 10.1177/0022034514559376
• Languages: English
• ISSNs: 0022-0345

Abstract

Mortality and morbidity associated with oral squamous cell carcinoma (OSCC) remain unacceptably high with disfiguring treatment options and a death rate of 1 per hour in the United States. The approval of cituximab for advanced OSCC has been the only new treatment for these patients since the 1970s, although it has not significantly increased overall survival. To address the paucity of effective new therapies, we undertook a high-throughput screen to discover small molecules and natural products that could induce endoplasmic reticulum (ER) stress and enforce a terminal unfolded protein response (UPR) in OSCC. The terpenoid cantharidin (CNT), previously used to treat various malignancies in culture-specific medical practices for over 2, 000 y, emerged as a hit. CNT and its analog, cantharidic acid, potently induced protein and gene expression profiles consistent with the activation of ER stress, the UPR, and apoptosis in OSCC cells. Murine embryonic fibroblasts null for the UPR-associated transcription factors Atf4 or Chop were significantly protected from CNT, implicating a key role for the UPR in the death response. These data validate that our high-throughput screen can identify novel modulators of UPR signaling and that such compounds might provide a new therapeutic approach to treating patients with OSCC.