bims-ershed 2023-07-30 papers

Toxicol In Vitro. 2023 Jul 21. pii: S0887-2333(23)00101-7. [Epub ahead of print] 105652

STF-083010 an inhibitor of IRE1α endonuclease activity affects mitochondrial respiration and generation of mitochondrial membrane potential.

Zuzana Hatokova, Andrea Evinova, Peter Racay.

STF-083010 is an inhibitor of endonuclease activity of inositol requiring-enzyme 1α (IRE1α) that is involved in activation of IRE1α-XBP1 axis of the unfolded protein response after ER stress. STF-083010 was tested as a possible antitumor agent in some previous studies exhibiting the ability either to induce death of tumour cells or to increase sensitivity of tumours cells to other neoplastic agents. STF-083010 exhibits also hepatoprotective effects in different models of liver injury and hepatic steatohepatitis. We have shown that STF-083010 has significant impact on mitochondrial functions that is not dependent on the way of STF-083010 application. We have observed that STF-083010 decrease of both maximal respiration (representing maximal electron transfer capacity of mitochondrial respiratory chain) and spare respiratory capacity after either incubation of the SH-SY5Y cells with STF-083010 or direct addition of STF-083010 to the respiration medium. In addition, we have documented impact of STF-083010 on generation of mitochondrial membrane potential (ΔΨm) that could be a result of decreased mitochondrial substrate level phosphorylation. Finally, increased sensitivity of ΔΨm to uncoupler in the presence of STF-083010 was documented. Our results indicate that STF-083010 has important impact on mitochondrial functions independently of its ability to inhibit endonuclease activity of IRE1α that is involved in activation of IRE1α-XBP1 axis of the unfolded protein response after ER stress. The impact of STF-083010 on mitochondrial functions could be associated with its possible off-target effect.

Keywords: Endoplasmic reticulum; Membrane potential; Mitochondria; Respiration

DOI: https://doi.org/10.1016/j.tiv.2023.105652

Med Oncol. 2023 Jul 22. 40(9): 247

Inhibition of IRE1 RNase activity modulates tumor cell progression and enhances the response to chemotherapy in colorectal cancer.

Sana Abbasi, Helia Rivand, Fatemeh Eshaghi, Mohammad Amin Moosavi, Saeid Amanpour, Michael F McDermott, Marveh Rahmati.

Drug resistance is one of the clinical challenges that limits the effectiveness of chemotherapy. Recent reports suggest that the unfolded protein response (UPR) and endoplasmic reticulum stress-adaptation signalling pathway, along with increased activation of its inositol-requiring enzyme 1α (IRE1α) arm, may be contributors to the pathogenesis of colorectal cancer (CRC). Here, we aimed to target the IRE1α/XBP1 pathway in order to sensitise CRC cells to the effects of chemotherapy. The CT26 colorectal cell line was treated with tunicamycin, and then was exposed to different concentrations of 5-fluorouracil (5-FU), either alone and/or in combination with the IRE1α inhibitor, 4µ8C. An MTT assay, flow cytometry and RT-PCR were performed to determine cell growth, apoptosis and IRE1α activity, respectively. In vivo BALB/c syngeneic colorectal mice received chemotherapeutic drugs. Treatment responses, tumour sizes and cytotoxicity were assessed via a range of pathological tests. 4µ8C was found to inhibit the growth of CRC, at a concentration of 10 µg/ml, without detectable cytotoxic effects and also significantly enhanced the cytotoxic potential of 5-FU, in CRC cells. In vivo experiments revealed that 4µ8C, at a concentration of 50 µM/kg prevented tumour growth without any cytotoxic or metastatic effects. Interestingly, the combination of 4µ8C with 5-FU remarkably enhanced drug responses, up to 40-60% and also lead to significantly greater inhibition of tumour growth, in comparison to monotherapy, in CRC mice. Targeting the IRE1α/XBP1 axis of the UPR could enhance the effectiveness of chemotherapy in both in vitro and in vivo models of CRC.

Keywords: 4µ8C; Colorectal Cancer; IRE1α; UPR; XBP1s

DOI: https://doi.org/10.1007/s12032-023-02105-7

Biomolecules. 2023 Jun 28. pii: 1050. [Epub ahead of print]13(7):

ER Stress, the Unfolded Protein Response and Osteoclastogenesis: A Review.

Wangli Huang, Yining Gong, Liang Yan.

Endoplasmic reticulum (ER) stress and its adaptive mechanism, the unfolded protein response (UPR), are triggered by the accumulation of unfolded and misfolded proteins. During osteoclastogenesis, a large number of active proteins are synthesized. When an imbalance in the protein folding process occurs, it causes osteoclasts to trigger the UPR. This close association has led to the role of the UPR in osteoclastogenesis being increasingly explored. In recent years, several studies have reported the role of ER stress and UPR in osteoclastogenesis and bone resorption. Here, we reviewed the relevant literature and discussed the UPR signaling cascade response, osteoclastogenesis-related signaling pathways, and the role of UPR in osteoclastogenesis and bone resorption in detail. It was found that the UPR signal (PERK, CHOP, and IRE1-XBP1) promoted the expression of the receptor activator of the nuclear factor-kappa B ligand (RANKL) in osteoblasts and indirectly enhanced osteoclastogenesis. IRE1 promoted osteoclastogenesis via promoting NF-κB, MAPK signaling, or the release of pro-inflammatory factors (IL-6, IL-1β, and TNFα). CREBH promoted osteoclast differentiation by promoting NFATc1 expression. The PERK signaling pathway also promoted osteoclastogenesis through NF-κB and MAPK signaling pathways, autophagy, and RANKL secretion from osteoblasts. However, salubrinal (an inhibitor of eIF2α dephosphorylation that upregulated p-eIF2α expression) directly inhibited osteoclastogenesis by suppressing NFATc1 expression and indirectly promoted osteoclastogenesis by promoting RANKL secretion from osteoblasts. Therefore, the specific effects and mechanisms of p-PERK and its downstream signaling on osteoclastogenesis still need further experiments to confirm. In addition, the exact role of ATF6 and BiP in osteoclastogenesis also required further exploration. In conclusion, our detailed and systematic review provides some references for the next step to fully elucidate the relationship between UPR and osteoclastogenesis, intending to provide new insights for the treatment of diseases caused by osteoclast over-differentiation, such as osteoporosis.

Keywords: ER stress; UPR; bone resorption; osteoclastogenesis

DOI: https://doi.org/10.3390/biom13071050

Res Sq. 2023 Jul 21. pii: rs.3.rs-3112506. [Epub ahead of print]

XBP1-mediated transcriptional regulation of SLC5A1 in human epithelial cells in disease conditions.

Yifei Sun, Yihan Zhang, Jifeng Zhang, Y Eugene Chen, Jian-Ping Jin, Kezhong Zhang, Hongmei Mou, Xiubin Liang, Jie Xu.

Background : sodium-dependent glucose cotransporter 1 and 2 (SGLT1/2) belong to the family of glucose transporters, encoded by SLC5A1 and SLC5A2, respectively. SGLT-2 is almost exclusively expressed in the renal proximal convoluted tubule cells. SGLT-1 is expressed in the kidneys but also in other organs throughout the body. Many SGLT inhibitor drugs have been developed based on the mechanism of blocking glucose (re)absorption mediated by SGLT1/2, and several have gained major regulatory agencies' approval for treating diabetes. Intriguingly these drugs are also effective in treating diseases beyond diabetes, for example heart failure and chronic kidney disease. We recently discovered that SGLT-1 is upregulated in the airway epithelial cells derived from patients of cystic fibrosis (CF), a devastating genetic disease affecting greater than 70,000 worldwide. Results : in the present work, we show that the SGLT-1 upregulation is coupled with elevated endoplasmic reticulum (ER) stress response, indicated by activation of the primary ER stress senor inositol-requiring protein 1a(IRE1a) and the ER stress-induced transcription factor X-box binding protein 1 (XBP1), in CF epithelial cells, and in epithelial cells of other stress conditions. Through biochemistry experiments, we demonstrated that XBP1 acts as a transcription factor for SLC5A1 by directly binding to its promoter region. Targeting this ER stress ® SLC5A1 axis by either the ER stress inhibitor Rapamycin or the SGLT-1 inhibitor Sotagliflozin was effective in attenuating the ER stress response and reducing the SGLT-1 levels in these cellular model systems. Conclusions : the present work establishes a causal relationship between ER stress and SGLT-1 upregulation and provides a mechanistic explanation why SGLT inhibitor drugs benefit diseases beyond diabetes.

DOI: https://doi.org/10.21203/rs.3.rs-3112506/v1

Pathol Res Pract. 2023 Jul 21. pii: S0344-0338(23)00406-5. [Epub ahead of print]248 154706

Role of the ER-induced UPR pathway, apoptosis, and autophagy in colorectal cancer.

Elmira Aboutalebi Vand Beilankouhi, Mir Amirhossein Sajadi, Iraj Alipourfard, Peyman Hassani, Mohammad Valilo, Reza Safaralizadeh.

When large amounts of misfolded or unfolded proteins accumulate in the endoplasmic reticulum (ER) in response to stress, a process called unfolded protein response (UPR) is activated. The disruption of this process leads to many diseases including diabetes, neurodegenerative diseases, and many cancers. In the process of UPR in response to stress and unfolded proteins, specific signaling pathways are induced in the endoplasmic reticulum and subsequently transmitted to the nucleus and cytoplasm, causing homeostasis and restoring the cell's normal condition with reducing protein translation and synthesis. The UPR response followed by stress enhancement balances cell survival with death, therefore in this condition cells decide either to survive or have the path of apoptosis ahead. However, in some cases, this balance is disturbed and the UPR pathway is chronically activated or not activated and the cell conditions lead to cancer. This study aimed to briefly investigate the association between ER stress, UPR, apoptosis, and autophagy in colorectal cancer (CRC). Moreover, in current study, we will try to demonstrate canonical ways and methods for the treatment of CRC cells with attenuated ER stress.

Keywords: Apoptosis; Chaperone; Colorectal cancer; ER stress; Unfolded protein response

DOI: https://doi.org/10.1016/j.prp.2023.154706