Autophagy Inhibitor, Chloroquine Synergize Oxaliplatin By Modulating Activity Of Cytosolic Hmgb1 In Pancreatic Cancer

Autophagy is a regulated, destructive catabolic mechanism to degrade cellular organelles and macromolecules. In cancer, the role of autophagy in tumor cell survival or death is still controversial because of each tumor type has a heterogeneity on metabolic status and microenvironment. In this study, we showed that autophagy inhibitor, chloroquine (CQ), increased sensitivity to oxaliplatin in pancreatic cancer cell lines. The autophagy inhibitor, chloroquine effectively inhibited autophagic flux which is important for maintenance of pancreatic cancer cell metabolism and drug resistance. Treatment of oxaliplatin after blockade of autophagy increased chromatin instability and facilitated loss of nuclear HMGB1. In consequence the cells turned into apoptotic cell death. The drug combination effect of chloroquine and oxaliplatin shows that inhibition of autophagy by chloroquine carry on dual role in pancreatic cancer cell death. First, chloroquine occurs cytosolic redox imbalance based on increase mitochondrial ROS (mtROS) following rupture of autolysosome. Second, the cytosolic redox imbalance occurred by chloroquine induces failure of autophagy by incapacitation of cytosolic HMGB1. Here we suggest that autophagy inhibition by chloroquine synergize oxaliplatin by modulating activity of cytosolic HMGB1. Also we suggest HMGB1 as a new target for therapeutic agents against pancreatic cancer. Citation Format: Seonmin Lee, Kyu-Pyo Kim, Changhoon Yoo, Danbi Kim, Chorong Kim, Heejung Chae, Jihoon Kang, Baek-Yeol Ryoo. Autophagy inhibitor, chloroquine synergize oxaliplatin by modulating activity of cytosolic HMGB1 in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1347.