Abstract 1243: Therapeutic ER stress induced by tunicamycin is anti-angiogenic/anti-tumorigenic and signals through unfolded protein response
Authors: Banerjee Dipak K. , Banerjee Aditi , Baksi Krishna , Katiyar Usha , Santiago Jesus , Sanchez Neysharie , Banerjee Dipak K. 
Published: August 2015

1.7 million Women were diagnosed with breast cancer worldwide in 2012 with a death rate of 522,000. If there are no major changes in prevention or treatment 846,241 women are estimated to die from the disease in 2035. The disease is multi-factorial with complex etiologically, and associated with uncontrolled cellular proliferation to invasion, to metastasis and angiogenesis. Based on current understanding, developing therapies to interrupt the angiogenic process has been proposed (http://www.angiogenesis.org; http://cancernet.nci.nih.gov). In addition, the Pharmaceutical Research and Manufacturers of America has reported 111 medicines and vaccines in clinical testing for breast cancer in 2012 (http://www.phrm.org/sites/default/files/pdf/phrmamedicinesindevelopmentcancer2012.pdf). A recent search of www.ClinicalTrials.gov shows 1,600 clinical trials are currently ongoing or recruiting for the evaluation of drug interventions for breast cancer. What remains unknown is whether the current approaches of developing more drugs and conducting more clinical trials can be redesigned to accelerate the rate of progress that will end breast cancer.

Protein glycosylation has been claimed as a universal feature of helping cancer cells escaping immune surveillance, facilitate tumor invasion, and increased malignancy with increased tumor burden and poor prognosis as well as for angiogenesis. Based on the glycomics profile of human breast cancer cells as well as tumor specimen, we have hypothesized that targeting asparagine-linked (N-linked) protein glycosylation would evolve a new generation therapeutic preventing breast tumor progression and eliminating the disease. To test our hypothesis, we have used a competitive inhibitor tunicamycin (a natural product) to block the first step of the N-glycan pathway. The results indicate that tunicamycin inhibited angiogenesis in vitro and in Matrigel™ implant in athymic Balb/c (nu/nu) mice which could not be reversed by VEGF and/or FGF-2, and supported by an increased expression of TSP1 in treated cells. The treatment inhibited VEGF-specific protein tyrosine phosphorylation as well. In parallel, tunicamycin inhibited breast cancer cells (BT-20/BT-474/ZR-731) proliferation and significantly reduced the progression of double and triple negative breast cancer in athymic nude mice with no detectable toxicity. High GRP-78/Bip expression suggested ER stress in tumor microvasculature and in tumor cells. As a result the cells were arrested in G1 and had undergone apoptosis mediated by unfolded protein response signaling. We, therefore, conclude that tunicamycin is an excellent glycotherapy treating breast cancer and its nanoformulation enhances the therapeutic efficacy. Supported by grants from Susan G. Komen for Cure BCTR0600582, NSF-EPSCoR RII Track 1 Grant# EPS-1002410 (DKB) and NIH/NIMHD 2G12MD007583 (KB).

Citation Format: Dipak K. Banerjee, Aditi Banerjee, Krishna Baksi, Usha Katiyar, Jesus Santiago, Neysharie Sanchez, Dipak K. Banerjee. Therapeutic ER stress induced by tunicamycin is anti-angiogenic/anti-tumorigenic and signals through unfolded protein response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1243. doi:10.1158/1538-7445.AM2015-1243