bims-unfpre 2022-06-05 papers

Issue of 2022–06–05
five papers selected by
Susan Logue, University of Manitoba

J Clin Invest. 2022 Jun 02. pii: e149906. [Epub ahead of print]

A mitochondrial unfolded protein response inhibitor suppresses prostate cancer growth in mice via HSP60.

Rahul Kumar, Ajay Kumar Chaudhary, Jordan Woytash, Joseph R Inigo, Abhiram A Gokhale, Wiam Bshara, Kristopher Attwood, Jianmin Wang, Joseph A Spernyak, Eva Rath, Neelu Yadav, Dirk Haller, David W Goodrich, Dean G Tang, Dhyan Chandra.

Mitochondrial proteostasis, regulated by the mitochondrial unfolded protein response (UPRmt), is crucial for maintenance of cellular functions and survival. Elevated oxidative and proteotoxic stress in mitochondria must be attenuated by the activation of ubiquitous UPRmt to promote prostate cancer (PCa) growth. Here we show that the two key components of the UPRmt, heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease (ClpP, a mitochondrial protease) were required for the development of advanced PCa. HSP60 regulated ClpP expression via c-Myc and physically interacted with ClpP to restore mitochondrial functions promoting cancer cell survival. HSP60 maintained the ATP-producing functions of mitochondria, which activated β-catenin pathway leading to the upregulation of c-Myc. We identified an UPRmt inhibitor that blocked HSP60 interaction with ClpP and abrogated survival signaling without altering HSP60 chaperonin function. Disruption of HSP60-ClpP interaction by UPRmt inhibitor triggered metabolic stress and impeded PCa promoting signaling. Treatment with UPRmt inhibitor, or genetic ablation of Hsp60, inhibited PCa growth and progression. Together, our findings identify that HSP60-ClpP mediated UPRmt is essential for prostate tumorigenesis and HSP60-ClpP interaction represents a therapeutic vulnerability in PCa.

Keywords: Cell Biology; Cell stress; Mitochondria; Oncology; Prostate cancer

DOI: https://doi.org/10.1172/JCI149906

Nat Cancer. 2022 Jun 02.

Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress.

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.

DOI: https://doi.org/10.1038/s43018-022-00389-8

J Extracell Vesicles. 2022 Jun;11(6): e12232

A multi-omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells.

Charles P Hinzman, Baldev Singh, Shivani Bansal, Yaoxiang Li, Anton Iliuk, Michael Girgis, Kelly M Herremans, Jose G Trevino, Vijay K Singh, Partha P Banerjee, Amrita K Cheema.

Although cancer-derived extracellular vesicles (cEVs) are thought to play a pivotal role in promoting cancer progression events, their precise effect on neighbouring normal cells is unknown. In this study, we investigated the impact of pancreatic cancer ductal adenocarcinoma (PDAC) derived EVs on recipient non-tumourigenic pancreatic normal epithelial cells upon internalization. We demonstrate that cEVs are readily internalized and induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in treated normal pancreatic epithelial cells within 24 h. We further show that PDAC cEVs increase cell proliferation, migration, and invasion and that these changes are regulated at least in part, by the UPR mediator DDIT3. Subsequently, these cells release several inflammatory cytokines. Leveraging a layered multi-omics approach, we analysed EV cargo from a panel of six PDAC and two normal pancreas cell lines, using multiple EV isolation methods. We found that cEVs were enriched for an array of biomolecules which can induce or regulate ER stress and the UPR, including palmitic acid, sphingomyelins, metabolic regulators of tRNA charging and proteins which regulate trafficking and degradation. We further show that palmitic acid, at doses relevant to those found in cEVs, is sufficient to induce ER stress in normal pancreas cells. These results suggest that cEV cargo packaging may be designed to disseminate proliferative and invasive characteristics upon internalization by distant recipient normal cells, hitherto unreported. This study is among the first to highlight a major role for PDAC cEVs to induce stress in treated normal pancreas cells that may modulate a systemic response leading to altered phenotypes. These findings highlight the importance of EVs in mediating disease aetiology and open potential areas of investigation toward understanding the role of cEV lipids in promoting cell transformation in the surrounding microenvironment.

Keywords: ER stress; extracellular vesicles; multi-omics; pancreatic cancer

DOI: https://doi.org/10.1002/jev2.12232

Cell Signal. 2022 May 26. pii: S0898-6568(22)00125-5. [Epub ahead of print] 110363

Quercetin attenuates sepsis-induced acute lung injury via suppressing oxidative stress-mediated ER stress through activation of SIRT1/AMPK pathways.

Aming Sang, Yun Wang, Shun Wang, Qingyuan Wang, Xiaohua Wang, Xinyi Li, Xuemin Song.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction play a pivotal role in the pathological process of sepsis-induced acute lung injury (ALI). Quercetin has been proved to exert anti-inflammation in ALI. This study aimed to explore the protection mechanism of quercetin against sepsis-induced ALI via suppressing ER stress and mitochondrial dysfunction. Cecal ligation and puncture (CLP) mouse model was established to mimic sepsis, and LPS was used to stimulate murine lung epithelial (MLE-12) cells. We observed that quercetin ameliorated pulmonary pathological lesion and oxidative damage in sepsis-induced mice. In LPS-stimulated MLE-12 cells, quercetin could inhibit the level of ER stress as evidenced by decreased mRNA expression of PDI, CHOP, GRP78, ATF6, PERK, IRE1α and improve mitochondrial function, as presented by increased MMP, SOD level and reduced production of ROS, MDA. Meanwhile, transcriptome analysis revealed that quercetin upregulated SIRT1/AMPK mRNA expression. Furthermore, we used siRNA to knockdown SIRT1 in MLE-12 cells, and we found that SIRT1 knockdown could abrogate the quercetin-elicited antioxidation in vitro. Therefore, quercetin could protect against sepsis-induced ALI by suppressing oxidative stress-mediated ER stress and mitochondrial dysfunction via induction of the SIRT1/AMPK pathways.

Keywords: Endoplasmic reticulum stress; Lung Injury; Quercetin; SIRT1; Sepsis

DOI: https://doi.org/10.1016/j.cellsig.2022.110363

FASEB J. 2022 Jul;36(7): e22388

Gestational cholestasis induced intrauterine growth restriction through triggering IRE1α-mediated apoptosis of placental trophoblast cells.

Xing-Xing Gao, Shuai Lin, Pei-Ying Jiang, Meng-Ying Ye, Wei Chen, Chuan-Xiang Hu, Yuan-Hua Chen.

Epidemiological and animal experimental studies suggest an association between gestational cholestasis and intrauterine growth restriction (IUGR). Here, we explored the mechanism through which gestational cholestasis induced IUGR. To establish gestational cholestasis model, pregnant mice were subcutaneously injected with 17α-Ethynylestradiol (E2) on gestational day 13 (GD13)-GD17. Some pregnant mice were intraperitoneally injected with 4μ8C on GD13-GD17. The results found that the apoptosis of trophoblast cells was elevated in placentas of mice with gestational cholestasis and in deoxycholic acid (DCA)-treated human trophoblast cell lines and primary mouse trophoblast cells. Correspondingly, the levels of placental cleaved caspase-3 and Bax were increased, while placental Bcl2 level was decreased in mice with gestational cholestasis and in DCA-treated trophoblast cells. Further analysis found that placental IRE1α pathway was activated in mice with gestational cholestasis and in DCA-treated trophoblast cells. Interestingly, 4μ8C, an IRE1α RNase inhibitor, significantly inhibited caspase-3 activity and apoptosis of trophoblast cells in vivo and in vitro. Importantly, 4μ8C rescued gestational cholestasis-induced placental insufficiency and IUGR. Furthermore, a case-control study demonstrated that placental IRE1α and caspase-3 pathways were activated in cholestasis cases. Our results provide evidence that gestational cholestasis induces placental insufficiency and IUGR may be via triggering IRE1α-mediated apoptosis of placental trophoblast cells.

Keywords: IRE1α; apoptosis; gestational cholestasis; intrauterine growth restriction (IUGR); placental insufficiency

DOI: https://doi.org/10.1096/fj.202101844RR