bims-unfpre 2020-04-12 papers

Issue of 2020‒04‒12
five papers selected by
Susan Logue
University of Manitoba

Cancer Res. 2020 Apr 07. pii: canres.3108.2019. [Epub ahead of print]

IRE1α disruption in triple-negative breast cancer cooperates with anti-angiogenic therapy by reversing ER stress adaptation and remodeling the tumor microenvironment.

Cancer cells exploit the unfolded protein response (UPR) to mitigate endoplasmic reticulum (ER) stress caused by cellular oncogene activation and a hostile tumor microenvironment (TME). The key UPR sensor IRE1α resides in the ER and deploys a cytoplasmic kinase-endoribonuclease module to activate the transcription factor XBP1s, which facilitates ER-mediated protein folding. Studies of triple-negative breast cancer (TNBC)-a highly aggressive malignancy with a dismal post-treatment prognosis-implicate XBP1s in promoting tumor vascularization and progression. However, it remains unknown whether IRE1α adapts the ER in TNBC cells and modulates their TME, and whether IRE1α inhibition can enhance anti-angiogenic therapy-previously found to be ineffective in TNBC patients. To gauge IRE1α function, we defined an XBP1s-dependent gene signature, which revealed significant IRE1α pathway activation in multiple solid cancers, including TNBC. IRE1α knockout in TNBC cells markedly reversed substantial ultrastructural expansion of the ER within these cells upon growth in vivo. IRE1α disruption also led to significant remodeling of the cellular TME, increasing pericyte numbers while decreasing cancer-associated fibroblasts and myeloid-derived suppressor cells. Pharmacological IRE1α kinase inhibition strongly attenuated growth of cell-line-based and patient-derived TNBC xenografts in mice and synergized with anti-VEGF-A treatment to cause tumor stasis or regression. Thus, TNBC cells critically rely on IRE1α to adapt their ER to in vivo stress and to adjust the TME to facilitate malignant growth. TNBC reliance on IRE1α is an important vulnerability that can be uniquely exploited in combination with anti-angiogenic therapy as a promising new biologic approach to combat this lethal disease.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-3108

FASEB Bioadv. 2020 Apr;2(4): 207-218

Elevation of the unfolded protein response increases RANKL expression.

Srividhya Iyer, Christian Melendez-Suchi, Li Han, Giulia Baldini, Maria Almeida, Robert L Jilka.

Increased production of the osteoclastogenic cytokine RANKL is a common feature of pathologic bone loss, but the underlying cause of this increase is poorly understood. The unfolded protein response (UPR) is activated in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER). Failure to resolve misfolding results in excess UPR signaling that stimulates cytokine production and cell death. We therefore investigated whether RANKL is one of the cytokines stimulated in response to elevated UPR in bone cells. Pharmacologic induction of UPR with tunicamycin (Tm)-stimulated RANKL expression in cultures of primary osteoblastic cells and in osteoblast and osteocyte cell lines. Pharmacologic inhibition of the UPR blunted Tm-induced RANKL production. Silencing Edem1 or Sel1l, proteins that aid in degradation of misfolded proteins, also induced UPR and increased RANKL mRNA. Moreover, Tm or hypoxia increased RANKL and bone resorption in cultures of neonatal murine calvaria. Administration of Tm to adult mice caused dilation of ER in osteoblasts and osteocytes, elevated the UPR, and increased RANKL expression and osteoclast number. These findings support the hypothesis that excessive UPR signaling stimulates the expression of RANKL by osteoblasts and osteocytes, and thereby facilitates excessive bone resorption and bone loss in pathologic conditions.

Keywords: calvaria; cytokines; endoplasmic reticulum stress; osteoblast; osteocyte

DOI: https://doi.org/10.1096/fba.2019-00032

Int Rev Cell Mol Biol. 2020 ;pii: S1937-6448(20)30007-1. [Epub ahead of print]351 57-99

TRAIL receptor signaling: From the basics of canonical signal transduction toward its entanglement with ER stress and the unfolded protein response.

Daniela Stöhr, Albert Jeltsch, Markus Rehm.

The cytokine tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the large TNF superfamily that can trigger apoptosis in transformed or infected cells by binding and activating two receptors, TRAIL receptor 1 (TRAILR1) and TRAIL receptor 2 (TRAILR2). Compared to other death ligands of the same family, TRAIL induces apoptosis preferentially in malignant cells while sparing normal tissue and has therefore been extensively investigated for its suitability as an anti-cancer agent. Recently, it was noticed that TRAIL receptor signaling is also linked to endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The role of TRAIL receptors in regulating cellular apoptosis susceptibility therefore is broader than previously thought. Here, we provide an overview of TRAIL-induced signaling, covering the core signal transduction during extrinsic apoptosis as well as its link to alternative outcomes, such as necroptosis or NF-κB activation. We discuss how environmental factors, transcriptional regulators, and genetic or epigenetic alterations regulate TRAIL receptors and thus alter cellular TRAIL susceptibility. Finally, we provide insight into the role of TRAIL receptors in signaling scenarios that engage the unfolded protein response and discuss how these findings might be translated into new combination therapies for cancer treatment.

Keywords: Apoptosis; ER stress; Programmed cell death; TRAIL; TRAIL receptors; Unfolded protein response

DOI: https://doi.org/10.1016/bs.ircmb.2020.02.002

Cancer Res. 2020 Apr 09. pii: canres.3580.2019. [Epub ahead of print]

H2A monoubiquitination links glucose availability to epigenetic regulation of the endoplasmic reticulum stress response and cancer cell death.

Yilei Zhang, Jiejun Shi, Xiaoguang Liu, Zhenna Xiao, Guang Lei, Hyemin Lee, Pranavi Koppula, Weijie Cheng, Chao Mao, Li Zhuang, Li Ma, Wei Li, Boyi Gan.

Epigenetic regulation of gene transcription has been shown to coordinate with nutrient availability, yet the mechanisms underlying this coordination remain incompletely understood. Here we show that glucose starvation suppresses histone 2A K119 monoubiquitination (H2Aub), a histone modification that correlates with gene repression. Glucose starvation suppressed H2Aub levels independently of energy stress-mediated AMPK activation and possibly through NADPH depletion and subsequent inhibition of BMI1, an integral component of polycomb repressive complex 1 (PRC1) that catalyzes H2Aub on chromatin. Integrated transcriptomic and epigenomic analyses linked glucose starvation-mediated H2Aub repression to the activation of genes involved in the endoplasmic reticulum (ER) stress response. We further showed that this epigenetic mechanism has a role in glucose starvation-induced cell death and that pharmacologic inhibition of glucose transporter 1 (GLUT1) and PRC1 synergistically promoted ER stress and suppressed tumor growth in vivo. Together, these results reveal a hitherto unrecognized epigenetic mechanism coupling glucose availability to the ER stress response.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-3580

Trends Endocrinol Metab. 2020 Apr 04. pii: S1043-2760(20)30060-6. [Epub ahead of print]

Mitochondria and T2D: Role of Autophagy, ER Stress, and Inflammasome.

Milagros Rocha, Nadezda Apostolova, Ruben Diaz-Rua, Jordi Muntane, Victor M Victor.

Type 2 diabetes (T2D) is one of the main current threats to human health. Both T2D and its numerous clinical complications are related to mitochondrial dysfunction and oxidative stress. Over the past decade, great progress has been made in extending our knowledge about the signaling events regulated by mitochondria. However, the links among mitochondrial impairment, oxidative stress, autophagy, endoplasmic reticulum (ER) stress, and activation of the inflammasome still need to be clarified. In light of this deficit, we aim to provide a review of the existing literature concerning the complicated crosstalk between mitochondrial impairment, autophagy, ER stress, and the inflammasome in the molecular pathogenesis of T2D.

Keywords: autophagy; endoplasmic reticulum stress; inflammasome; mitochondria; oxidative stress; type 2 diabetes

DOI: https://doi.org/10.1016/j.tem.2020.03.004