Activation of IRE1α-XBP1 pathway induces cell proliferation and invasion in colorectal carcinoma

Jin, Chen; Jin, Zhao; Chen, Nian-zhao; Lü, Min; Liu, Changbao; Hu, Wanle; Zheng, Chenguo

doi:10.1016/j.bbrc.2015.12.119

Cited by 60 publications

(46 citation statements)

References 23 publications

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“…Similarly, dihydroartemisinin chemotherapy induces mitochondria-dependent apoptosis via ER stress pathways in CRC HCT116 cells 162 . The ERN1-XBP1 pathway is also important for promotion and progression of CRC 163 . Recent report shows a pivotal role of XBP1 in CRC invasion 164 .…”

Section: General Aspects Of the Unfolded Protein Responsementioning

confidence: 99%

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

et al. 2017

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Colorectal cancer (CRC), despite numerous therapeutic and screening attempts, still remains a major life-threatening malignancy. CRC etiology entails both genetic and environmental factors. Macroautophagy/autophagy and the unfolded protein response (UPR) are fundamental mechanisms involved in the regulation of cellular responses to environmental and genetic stresses. Both pathways are interconnected and regulate cellular responses to apoptotic stimuli. In this review, we address the epidemiology and risk factors of CRC, including genetic mutations leading to the occurrence of the disease. Next, we discuss mutations of genes related to autophagy and the UPR in CRC. Then, we discuss how autophagy and the UPR are involved in the regulation of CRC and how they associate with obesity and inflammatory responses in CRC. Finally, we provide perspectives for the modulation of autophagy and the UPR as new therapeutic options for CRC treatment.

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Section: General Aspects Of the Unfolded Protein Responsementioning

confidence: 99%

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

et al. 2017

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“…hypoxia) and pharmacological induction of ER stress [252][253][254][255]. The IRE1-XBP1 pathway has been reported to negatively regulate the traditional epithelial marker E-cadherin, while positively regulating the mesenchymal marker N-cadherin in models of colorectal, breast and pulmonary fibrosis [254,256,257]. Breast cancer and pulmonary fibrosis models showed an IRE1-XBP1-dependent regulation of mesenchymal promoting transcription factor SNAIL that is responsible for EMT [254,256].…”

Section: Upr-associated Morphological Changesmentioning

confidence: 99%

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

et al. 2018

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The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.

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“…Its role in cancer progression was also documented along this axis, showing an activation of the pathway inducing proliferation in colorectal carcinoma cells [26]. It was identified as a druggable target and potential therapeutic option in multiple myeloma [27, 28] and seems to be amplified in 8% of invasive breast cancers [18, 19].…”

Section: Discussionmentioning

confidence: 99%

ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer

Strietz¹,

Stepputtis

Preca

et al. 2016

Oncotarget

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Cancers are heterogeneous by nature. While traditional oncology screens commonly use a single endpoint of cell viability, altering the phenotype of tumor-initiating cells may reveal alternative targets that regulate cellular growth by processes other than apoptosis or cell division. We evaluated the impact of knocking down expression of 420 kinases in bi-lineage triple-negative breast cancer (TNBC) cells that express characteristics of both myoepithelial and luminal cells. Knockdown of ERN1 or ALPK1 induces bi-lineage MDA-MB-468 cells to lose the myoepithelial marker keratin 5 but not the luminal markers keratin 8 and GATA3. In addition, these cells exhibit increased β-casein production. These changes are associated with decreased proliferation and clonogenicity in spheroid cultures and anchorage-independent growth assays. Confirmation of these assays was completed in vivo, where ERN1- or ALPK1-deficient TNBC cells are less tumorigenic. Finally, treatment with K252a, a kinase inhibitor active on ERN1, similarly impairs anchorage-independent growth of multiple breast cancer cell lines. This study supports the strategy to identify new molecular targets for types of cancer driven by cells that retain some capacity for normal differentiation to a non-tumorigenic phenotype. ERN1 and ALPK1 are potential targets for therapeutic development.

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Activation of IRE1α-XBP1 pathway induces cell proliferation and invasion in colorectal carcinoma

Cited by 60 publications

References 23 publications

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer

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