IRE1α-XBP1 signaling pathway, a potential therapeutic target in multiple myeloma

Chen, Lin; Li, Qian; She, Tiantian; Li, Han; Yue, Yuanfang; Gao, Shuang; Yan, Tinghui; Liu, Su; Ma, Jing; Wang, Yafei

doi:10.1016/j.leukres.2016.07.006

Cited by 42 publications

(40 citation statements)

References 71 publications

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“…This approach is promising in the treatment of hematological malignancies. [1][2][3][4] The ER stress response is employed by many types of immune cells to cope with cell stress to avoid apoptosis. [5][6][7][8][9][10][11] The 3 primary regulators of the ER stress response are IRE-1a, PERK, and ATF6.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

Schutt

Tang

et al. 2018

Blood Advances

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Key Points• Targeting XBP-1 on B cells is sufficient to prevent cGVHD.• Pharmacologic inhibition of IRE-1a/ XBP-1 prevents cGVHD while preserving GVL activity. which correlated with reductions in donor T-cell and dendritic cell skin infiltrates. Inhibition of the IRE-1a/XBP-1 pathway also preserved the GVL effect against chronic myelogenous leukemia mediated by allogeneic splenocytes. Collectively, the ER stress response mediated by the IRE-1a/XBP-1 axis is required for cGVHD development but dispensable for GVL activity.

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Section: Introductionmentioning

confidence: 99%

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

Schutt

Tang

et al. 2018

Blood Advances

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“…These are downstream components of ER chaperones, which transmit stress signals from the ER to the nucleus. IRE1 activates the endonuclease domains, which cleave X-box DNA-binding protein (XBP) mRNA, generating an activated form of the XBP1 protein (30). Activating PERK results in phosphorylation of the eIF2α subunit and inhibits translation initiation (31).…”

Section: Resultsmentioning

confidence: 99%

Luteolin-induced apoptosis through activation of endoplasmic reticulum stress sensors in pheochromocytoma cells

Kwon

Kim

et al. 2017

Molecular Medicine Reports

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Luteolin [2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-chromenone] is an active flavonoid compound from Lonicera japonica (Caprifoliaceae). Luteolin inhibits tumor cell proliferation, inflammatory and oxidative stress better, when compared with other flavonoids. In the present study, it was demonstrated that luteolin induces typical apoptosis in PC12 cells (derived from a pheochromocytoma of the rat adrenal medulla) accompanied by DNA fragmentation and formation of apoptotic bodies. In addition, luteolin regulates expression of the endoplasmic reticulum (ER) chaperone binding immunoglobulin protein, activating ER stress sensors (eukaryotic initiation factor 2α phosphorylation and X‑box binding protein 1 mRNA splicing) and induced autophagy. The results indicated that luteolin induces the upregulation of the unfolded protein response pathway through the ER stress sensors, which helps as an influential regulator for the apoptosis pathway in PC12 cells. The results suggested that the understanding of the molecular mechanisms underlying luteolin‑induced apoptosis may be useful in cancer therapeutics, chemoprevention and neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease.

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“…If the apoptotic stage of the UPR is avoided by various mechanisms such as upregulation of the CHOP suppressor p58 IPK , cancerous cells can exploit the prosurvival aspects of the UPR unhindered to resist the hostile environment inside a growing tumor. Upregulation of components of the UPR, such as BiP or the IRE1α‐XBP1 pathway, occurs in many cancers and is linked to increased chemoresistance, aggressiveness, and poor outcomes for patients …”

Section: Overview Of the Uprmentioning

confidence: 99%

“…Upregulation of components of the UPR, such as BiP or the IRE1α-XBP1 pathway, occurs in many cancers and is linked to increased chemoresistance, aggressiveness, and poor outcomes for patients. [21][22][23][24] More recent studies show that ER stress and the UPR are transmissible between cells via extracellular vesicles. 25 This expands on the previous discovery of the transmission of hypoxia resistance between cancerous cells 26 and the wider concept of extracellular vesicles as a method of communication within the tumor microenvironment.…”

Section: Overview Of the Uprmentioning

confidence: 99%

The multiple roles of the unfolded protein response regulator IRE1α in cancer

Chalmers

Mogre

Son

et al. 2019

Molecular Carcinogenesis

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Cancer is associated with a number of conditions such as hypoxia, nutrient deprivation, cellular redox, and pH changes that result in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) and trigger a stress response known as the unfolded protein response (UPR). The UPR is a conserved cellular survival mechanism mediated by the ER transmembrane proteins activating transcription factor 6, protein kinase‐like endoplasmic reticulum kinase, and inositol‐requiring enzyme 1α (IRE1α) that act to resolve ER stress and promote cell survival. IRE1α is a kinase/endoribonuclease (RNase) with multiple activities including unconventional splicing of the messenger RNA (mRNA) for the transcription factor X‐Box Binding Protein 1 (XBP1), degradation of other mRNAs in a process called regulated IRE1α‐dependent decay (RIDD) and activation of a pathway leading to c‐Jun N‐terminal kinase phosphorylation. Each of these outputs plays a role in the adaptive and cell death responses to ER stress. Many studies indicate an important role for XBP1 and RIDD functions in cancer and new studies suggest that these two functions of the IRE1α RNase can have opposing functions in the early and later stages of cancer pathogenesis. Finally, as more is learned about the context‐dependent role of IRE1α in cancer development, specific small molecule inhibitors and activators of IRE1α could play an important role in counteracting the protective shield provided by ER stress signaling in cancer cells.

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IRE1α-XBP1 signaling pathway, a potential therapeutic target in multiple myeloma

Cited by 42 publications

References 71 publications

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

Luteolin-induced apoptosis through activation of endoplasmic reticulum stress sensors in pheochromocytoma cells

The multiple roles of the unfolded protein response regulator IRE1α in cancer

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