Abstract
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.
Highlights
The endoplasmic reticulum (ER) is the primary site for synthesis, folding and post-translational processing of proteins
Kinetic analysis in MDA-MB-435S melanoma cells [19], showed that C/EBPδ induction peaked between 4–8 h, relatively concurrent with XBP1S, ATF4 and deplete STAT3, which had no effect on thapsigargin-induced ATF4 expression but reduced C/EBPδ induction at the RNA and protein levels (Fig. 3d, e)
Autocrine and paracrine signaling by the tumor cell secretome are critical determinants of tumor biology by modulating the microenvironment and tumor cell phenotypes that contribute to tumor development and therapeutic outcomes
Summary
The endoplasmic reticulum (ER) is the primary site for synthesis, folding and post-translational processing of proteins. Cancer cells experience chronic ER stress due to intracellular activation of oncogenes and loss of tumor suppressors as well as microenvironmental stressors such as nutrient deprivation and hypoxia [1]. The ER stress sensors ATF6, IRE1 and PERK trigger transcriptional reprogramming mediated by ATF6-N, XBP1S and ATF4, respectively, to effect the stress response pathways [3,4,5]. Cancer cells hijack these pathways to promote cell survival under stress and thereby facilitate tumor metastasis and therapy resistance [6, 7]. Thapsigargin, the active component of the pro-drug mipsagargin, which is in clinical trials for advanced refractory cancers of the breast, brain, prostate and liver, is an inhibitor of the SERCA pump and causes ER stress through loss of calcium from the ER [10, 11]
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