Abstract 3985: Differential activation of unfolded protein response in metastatic vs. non-metastatic osteosarcoma cells following hypoxia and chemotherapeutic stress

Abstract

Abstract Osteosarcoma (OS) is the most common primary tumor of bone and the second highest cause of cancer-related death in the pediatric age group. Despite significant advances in diagnosis and treatment for this cancer, the overall survival has remained static over the past 20 years. This is due to the fact that little is known about the basic science mechanisms of the pathology of human osteosarcoma as well as the mechanisms of inherent drug resistance of OS. In particular lesser still is known regarding the role of tumor microenvironment that govern growth and progression of osteosarcoma in vivo. Recent clinical reports have demonstrated a negative correlation between tumor hypoxia and overall survival in osteosarcoma patients. In addition to the upregulation of HIFs, it has been shown that hypoxia can trigger an adaptive response such as the unfolded protein response (UPR) that allows tumor cells to avoid therapy-induced death. Using in vitro experimental models of both the non-metastatic (SAOS-2) and metastatic (143-b) osteosarcoma cell lines, we now show that hypoxic signaling in these cells differentially activates a pro-survival mechanism via the up-regulation of the endoplasmic reticulum (ER) chaperone BiP and increased activation of the ER stress-activated eukaryotic translation initiator factor 2alpha kinase RNA-dependent protein kinase-like ER kinase (PERK) and ATF-6, markers of UPR allowing the cells to resist drug toxicity. Furthermore RNA interference and dominant-negative expression studies revealed that both ATF-6 and PERK signaling promote survival and drug resistance of OS cells, Our findings shed light on the unknown mechanisms underlying chemotherapeutic drug resistance in osteosarcoma patients. We propose that hypoxic induction of UPR protects OS cells from stress insults, such as chemotherapy. Our research may lead to novel therapies that seek out and destroy the chemoresistant OS cells within the hypoxic core of tumors, thereby preventing survival and metastasis, and ultimately improving the chances of survival amongst OS patients. Citation Format: Janine Faraj, Pooja Hingorani, Aparna R. Sertil. Differential activation of unfolded protein response in metastatic vs. non-metastatic osteosarcoma cells following hypoxia and chemotherapeutic stress. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3985. doi:10.1158/1538-7445.AM2014-3985