Endoplasmic reticulum stress and autophagy as targets for cancer therapy

The endoplasmic reticulum stress (ERS) response represents an adaptive mechanism that supports survival and chemoresistance of tumor cells. Autophagy, although less well understood, has also been emerging as a means for tumor cells to increase survival under conditions of metabolic stress, hypoxia, and perhaps even chemotherapy. Although these two systems may function independently from each other, there are also important connections with interdependent controls, where altered activity of one system impinges upon the other. Both ERS and autophagy follow a yin-yang principle, by which their low to moderate activity is cell protective and supports chemoresistance (yin), but where severe conditions will aggravate these mechanisms to the point where they abandon their protective efforts and instead will trigger cell death (yang). Because some of these mechanisms seem to display tumor-specific activities, they may provide opportunities for pharmacologic intervention aimed at ERS or autophagy. This mini-review will describe the yin-yang principle of ERS and autophagy, and will present newly recognized approaches to pharmacologically exploit these mechanisms for improved antitumor outcomes. (C) 2008 Elsevier Ireland Ltd. All rights reserved.