Low intensity focused ultrasound (LOFU) modulates unfolded protein response and sensitizes prostate cancer to 17AAG

Subhrajit Saha1, Payel Bhanja1, Ari Partanen2, Wei Zhang1, Laibin Liu1, Wolfgang A. Tomé1,4 and Chandan Guha1,3,4

1 Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York, USA

2 Philips Healthcare, Cleveland, OH, USA

3 Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA

4 Montefiore Medical Center, New York, NY, USA


Chandan Guha, email:

Keywords: Prostate Cancer, 17AAG, Focused Ultrasound, UPR, ER stress

Received: April 30, 2014 Accepted: June 02, 2014 Published: June 03, 2014


The hypoxic tumor microenvironment generates oxidative Endoplasmic Reticulum (ER) stress, resulting in protein misfolding and unfolded protein response (UPR). UPR induces several molecular chaperones including heat-shock protein 90 (HSP90), which corrects protein misfolding and improves survival of cancer cells and resistance to tumoricidal therapy although prolonged activation of UPR induces cell death. The HSP90 inhibitor, 17AAG, hasshown promise against various solid tumors, including prostate cancer (PC). However, therapeutic doses of 17AAG elicit systemic toxicity. In this manuscript, we describe a new paradigm where the combination therapy of a non-ablative and non-invasive low energy focused ultrasound (LOFU) and a non-toxic, low dose 17AAG causes synthetic lethality and significant tumoricidal effects in mouse and human PC xenografts. LOFU induces ER stress and UPR in tumor cells without inducing cell death. Treatment with a non-toxic dose of 17AAG further increased ER stress in LOFU treated PC and switched UPR from a cytoprotective to an apoptotic response in tumors resulting in significant induction of apoptosis and tumor growth retardation. These observations suggest that LOFU-induced ER stress makes the ultrasound-treated tumors more susceptible to chemotherapeutic agents, such as 17AAG. Thus, a novel therapy of LOFU-induced chemosensitization may be designed for locally advanced and recurrent tumors.

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