IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling
Xia Sheng,Hatice Zeynep Nenseth,Su Qu,Omer F. Kuzu,Turid Frahnow,Lukas M. Simon,Stephanie Greene,Qingping Zeng,Ladan Fazli,Paul S. Rennie,Ian G. Mills,Håvard E. Danielsen,Fabian J. Theis,John B. Patterson,Yang Jin,Yang Jin,Fahri Saatcioglu,Fahri Saatcioglu +17 more
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TLDR
It is reported that an IRE1α RNase-specific inhibitor, MKC8866, strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs.Abstract:
Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity of reagents to translate this for cancer therapy. Here, we report that an IRE1α RNase-specific inhibitor, MKC8866, strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal that IRE1α-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in PCa. XBP1s is necessary for optimal c-MYC mRNA and protein expression, establishing, for the first time, a direct link between UPR and oncogene activation. In addition, an XBP1-specific gene expression signature is strongly associated with PCa prognosis. Our data establish IRE1α-XBP1s signaling as a central pathway in PCa and indicate that its targeting may offer novel treatment strategies.read more
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Journal ArticleDOI
Mechanisms, regulation and functions of the unfolded protein response.
TL;DR: The unfolded protein response comprises a network of signalling pathways that reprogramme transcription, translation and protein modifications to relieve the load of unfolded or misfolded proteins in the endoplasmic reticulum lumen and restore proteostasis.
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Endoplasmic reticulum stress signals in the tumour and its microenvironment
Xi Chen,Juan R. Cubillos-Ruiz +1 more
TL;DR: How ER stress can influence not only the pro-tumoural features of cancer cells but also reprogramme the function of innate and adaptive immune cells, creating vulnerabilities that could be targeted by emerging therapeutic strategies is discussed.
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Pharmacological targeting of the unfolded protein response for disease intervention.
TL;DR: Recent developments in the design and optimization of novel compounds to manipulate UPR signaling and the application of these small molecules in cancers, neurodegeneration and metabolic diseases are discussed.
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Insights into new mechanisms and models of cancer stem cell multidrug resistance
TL;DR: An integrated picture of the MDR mechanisms that operate in CSCs' behavior is provided and a novel model of tumor evolution during chemotherapy is proposed, suggesting underlying additional causes for CSC resilience.
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Endoplasmic Reticulum Stress Signaling in Cancer Cells.
TL;DR: The mounting evidence that cancer cells are predisposed to ER stress and vulnerable to targeted interventions against ongoing UPR signaling is summarized.
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