Cancer cells experience endoplasmic reticulum (ER) stress due to activated oncogenes and conditions of nutrient deprivation and
hypoxia. The ensuing unfolded protein response (UPR) is executed by ATF6, IRE1 and PERK pathways. Adaptation to mild ER stress promotes
tumor cell survival and aggressiveness. Unmitigated ER stress, however, will result in cell death and is a potential avenue for
cancer therapies. Because of this yin-yang nature of ER stress, it is imperative that we fully understand the mechanisms and dynamics of the UPR and its contribution to the complexity of
tumor biology. The PERK pathway inhibits global
protein synthesis while allowing translation of specific mRNAs, such as the
ATF4 transcription factor. Using
thapsigargin and
tunicamycin to induce acute ER stress, we identified the
transcription factor C/EBPδ (CEBPD) as a mediator of PERK signaling to secretion of
tumor promoting
chemokines. In
melanoma and
breast cancer cell lines, PERK mediated early induction of C/EBPδ through ATF4-independent pathways that involved at least in part
Janus kinases and the
STAT3 transcription factor. Transcriptional profiling revealed that C/EBPδ contributed to 20% of
thapsigargin response genes including chaperones, components of ER-associated degradation, and apoptosis inhibitors. In addition, C/EBPδ supported the expression of the
chemokines CXCL8 (IL-8) and CCL20, which are known for their
tumor promoting and immunosuppressive properties. With a paradigm of short-term exposure to
thapsigargin, which was sufficient to trigger prolonged activation of the UPR in
cancer cells, we found that
conditioned media from such cells induced
cytokine expression in myeloid cells. In addition, activation of the CXCL8
receptor CXCR1 during
thapsigargin exposure supported subsequent sphere formation by
cancer cells. Taken together, these investigations elucidated a novel mechanism of ER stress-induced transmissible signals in
tumor cells that may be particularly relevant in the context of pharmacological interventions.