Autophagy is intricately linked with many intracellular signaling pathways, particularly nutrient-sensing mechanisms and cell death signaling cascades. In cancer, the roles of autophagy are context dependent. Tumor cell–intrinsic effects of autophagy can be both tumor suppressive and tumor promotional. Autophagy can therefore not only activate and inhibit cell death, but also facilitate the switch between cell death mechanisms. Moreover, autophagy can play opposing roles in the tumor microenvironment via non–cell-autonomous mechanisms. Preclinical data support a tumor-promotional role of autophagy in established tumors and during cancer therapy; this has led to the launch of dozens of clinical trials targeting autophagy in multiple cancer types. However, many questions remain: which tumors and genetic backgrounds are the most sensitive to autophagy inhibition, and which therapies should be combined with autophagy inhibitors? Additionally, since cancer cells are under selective pressure and are prone to adaptation, particularly after treatment, it is unclear if and how cells adapt to autophagy inhibition. Here we review recent literature addressing these issues.
The adapter protein tumor necrosis factor receptor (TNFR)1–associated death domain (TRADD) plays an essential role in recruiting signaling molecules to the TNFRI receptor complex at the cell membrane. Here we show that TRADD contains a nuclear export and import sequence that allow shuttling between the nucleus and the cytoplasm. In the absence of export, TRADD is found within nuclear structures that are associated with promyelocytic leukemia protein (PML) nuclear bodies. In these structures, the TRADD death domain (TRADD-DD) can activate an apoptosis pathway that is mechanistically distinct from its action at the membrane-bound TNFR1 complex. Apoptosis by nuclear TRADD-DD is promyelocytic leukemia protein dependent, involves p53, and is inhibited by Bcl-xL but not by caspase inhibitors or dominant negative FADD (FADD-DN). Conversely, apoptosis induced by TRADD in the cytoplasm is resistant to Bcl-xL, but sensitive to caspase inhibitors and FADD-DN. These data indicate that nucleocytoplasmic shuttling of TRADD leads to the activation of distinct apoptosis mechanisms that connect the death receptor apparatus to nuclear events.