bims-istrec 2022-12-25 papers

bims-istrec

Biomed News

on Integrated stress response in cancer

Issue of 2022‒12‒25
ten papers selected by
the Vincenzo Ciminale lab
Istituto Oncologico Veneto

The deubiquitinase USP10 protects pancreatic cancer cells from endoplasmic reticulum stress.
Correction to: An investigation of Sigma-1 receptor expression and ligand-induced endoplasmic reticulum stress in breast cancer.
Inclusion of the in-chain sulfur in 3-thiaCTU increases the efficiency of mitochondrial targeting and cell killing by anticancer aryl-urea fatty acids.
Sestrin2 Overexpression Ameliorates Endoplasmic Reticulum Stress-Induced Apoptosis via Inhibiting mTOR Pathway in HepG2 Cells.
Mechanism and Role of Endoplasmic Reticulum Stress in Osteosarcoma.
Deregulation of HSF1-mediated endoplasmic reticulum unfolded protein response promotes cisplatin resistance in lung cancer cells.
Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma.
The unfolded protein response (UPR) pathway: the unsung hero in breast cancer management.
HERPUD1 promotes ovarian cancer cell survival by sustaining autophagy and inhibit apoptosis via PI3K/AKT/mTOR and p38 MAPK signaling pathways.
LINC00629 protects osteosarcoma cell from ER stress-induced apoptosis and facilitates tumour progression by elevating KLF4 stability.

NPJ Precis Oncol. 2022 Dec 21. 6(1): 93

The deubiquitinase USP10 protects pancreatic cancer cells from endoplasmic reticulum stress.

Udayan Bhattacharya, Elangovan Thavathiru, Fiifi Neizer-Ashun, Chao Xu, Zoran Gatalica, Shailendra Kumar Dhar Dwivedi, Anindya Dey, Priyabrata Mukherjee, Resham Bhattacharya.

The ubiquitin-specific peptidase 10 (USP10) plays a context-specific, pro or anti-tumorigenic role in different malignancies. However, the role of USP10 in pancreatic cancer remains unclear. Our protein and RNA level analysis from archived specimens and public databases show that USP10 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and expression correlates with poor overall patient survival. Phenotypically, silencing USP10 decreased viability, clonal growth and invasive properties of pancreatic cancer cells. Mechanistically, silencing USP10 upregulated BiP and induced endoplasmic reticulum (ER) stress that led to an unfolded protein response (UPR) and upregulation of PERK, IRE1α. Decreased cell viability of USP10 silenced cells could be rescued by a chemical chaperone that promotes protein folding. Our studies suggest that USP10 by protecting pancreatic cancer cells from ER stress may support tumor progression.

DOI: https://doi.org/10.1038/s41698-022-00336-x
Cancer Gene Ther. 2022 Dec 21.

Correction to: An investigation of Sigma-1 receptor expression and ligand-induced endoplasmic reticulum stress in breast cancer.

Preeti Borde, Nicola Cosgrove, Sara Charmsaz, Stephen T Safrany, Leonie Young.

DOI: https://doi.org/10.1038/s41417-022-00579-7
Eur J Pharmacol. 2022 Dec 18. pii: S0014-2999(22)00731-2. [Epub ahead of print]939 175470

Inclusion of the in-chain sulfur in 3-thiaCTU increases the efficiency of mitochondrial targeting and cell killing by anticancer aryl-urea fatty acids.

Md Khalilur Rahman, Balasubrahmanyam Umashankar, Hassan Choucair, Curtis Pazderka, Kirsi Bourget, Yongjuan Chen, Colin R Dunstan, Tristan Rawling, Michael Murray.

  Mitochondria in tumor cells are functionally different from those in normal cells and could be targeted to develop new anticancer agents. We showed recently that the aryl-ureido fatty acid CTU is the prototype of a new class of mitochondrion-targeted agents that kill cancer cells by increasing the production of reactive oxygen species (ROS), activating endoplasmic reticulum (ER)-stress and promoting apoptosis. However, prolonged treatment with high doses of CTU were required for in vivo anti-tumor activity. Thus, new strategies are now required to produce agents that have enhanced anticancer activity over CTU. In the present study we prepared a novel aryl-urea termed 3-thiaCTU, that contained an in-chain sulfur heteroatom, for evaluation in tumor cell lines and in mice carrying tumor xenografts. The principal finding to emerge was that 3-thiaCTU was several-fold more active than CTU in the activation of aryl-urea mechanisms that promoted cancer cell killing. Thus, in in vitro studies 3-thiaCTU disrupted the mitochondrial membrane potential, increased ROS production, activated ER-stress and promoted tumor cell apoptosis more effectively than CTU. 3-ThiaCTU was also significantly more active than CTUin vivo in mice that carried MDA-MB-231 cell xenografts. Compared to CTU, 3-thiaCTU prevented tumor growth more effectively and at much lower doses. These findings indicate that, in comparison to CTU, 3-thiaCTU is an aryl-urea with markedly enhanced activity that could now be suitable for development as a novel anticancer agent.

Keywords:  Endoplasmic reticulum stress; Mitochondria; Pro-apoptotic agents; Reactive oxygen species; Ureido-fatty acids

DOI:  https://doi.org/10.1016/j.ejphar.2022.175470
Int J Endocrinol. 2022 ;2022 2009753

Sestrin2 Overexpression Ameliorates Endoplasmic Reticulum Stress-Induced Apoptosis via Inhibiting mTOR Pathway in HepG2 Cells.

Huiling Hu, Zhijun Luo, Xiuli Liu, Lisi Huang, Xiaoxia Lu, Rui Ding, Chaohui Duan, Yuqing He.

Sestrin2 is a highly conserved stress-inducible protein, acting as a crucial part in regulating homeostasis in response to various stress conditions in the cell. However, the role of Sestrin2 in regulating cell apoptosis related to endoplasmic reticulum (ER) has not been fully investigated. Our study presented here aims to reveal the effect of Sestrin2 in tunicamycin (TM)-induced cell apoptosis related to ER stress and its underlying molecular mechanisms. The results demonstrated that Sestrin2 expression was significantly upregulated correlated with ER stress responses in TM treated HepG2 cells. Sestrin2 overexpression obviously alleviated ER stress with the determination of ER stress-related proteins expression. In addition, Sestrin2 overexpression inhibited cell apoptosis with the examination of apoptosis-related proteins and TUNEL assay. However, Sestrin2 knockdown further promoted the ER stress-mediated cell apoptosis. The further mechanistic study revealed that Sestrin2 overexpression inhibited TM-induced mTOR pathway activation. Taken together, our current study indicated that Sestrin2 overexpression ameliorates ER stress-induced apoptosis via inhibiting mTOR pathway in HepG2 cells.

DOI: https://doi.org/10.1155/2022/2009753
Biomolecules. 2022 Dec 15. pii: 1882. [Epub ahead of print]12(12):

Mechanism and Role of Endoplasmic Reticulum Stress in Osteosarcoma.

Peijun Zhu, Ting Li, Qingqing Li, Yawen Gu, Yuan Shu, Kaibo Hu, Leifeng Chen, Xiaogang Peng, Jie Peng, Liang Hao.

  Osteosarcoma is the most common malignant bone tumor, often occurring in children and adolescents. The etiology of most patients is unclear, and the current conventional treatment methods are chemotherapy, radiotherapy, and surgical resection. However, the sensitivity of osteosarcoma to radiotherapy and chemotherapy is low, and the prognosis is poor. The development of new and useful treatment strategies for improving patient survival is an urgent need. It has been found that endoplasmic reticulum (ER) stress (ERS) affects tumor angiogenesis, invasion, etc. By summarizing the literature related to osteosarcoma and ERS, we found that the unfolded protein response (UPR) pathway activated by ERS has a regulatory role in osteosarcoma proliferation, apoptosis, and chemoresistance. In osteosarcoma, the UPR pathway plays an important role by crosstalk with autophagy, oxidative stress, and other pathways. Overall, this article focuses on the relationship between ERS and osteosarcoma and reviews the potential of drugs or gene targets associated with ERS for the treatment of osteosarcoma.

Keywords:  autophagy; endoplasmic reticulum stress; osteosarcoma; oxidative stress; therapy; unfolded protein response

DOI:  https://doi.org/10.3390/biom12121882
FEBS J. 2022 Dec 19.

Deregulation of HSF1-mediated endoplasmic reticulum unfolded protein response promotes cisplatin resistance in lung cancer cells.

Min Zhang, Xiaoyu Duan, Lu Wang, Jing Wen, Pingfei Fang.

  Mild hypothermia can induce apoptotic cell death in many cancer cells, but the underlying mechanisms remain unclear. In a genetic screen in C. elegans, we found that impaired endoplasmic reticulum unfolded protein response (UPRER ) increased animal survival after cold shock. Consistently, in normal human lung cells, decreasing culture temperature from 37°C to 30°C activated UPRER and promoted cell death. However, lung adenocarcinoma cells were impaired in UPRER induction and resistant to hypothermia-induced cell death. Mechanistically, hypothermic stress increased HSF1 levels, which in turn activated UPRER to promote apoptotic cell death. HSF1 expression was associated with UPRER genes in normal tissues but such association was lost in many cancers, especially lung adenocarcinoma. Activating UPRER enhanced the cytotoxicity of chemotherapy drugs cisplatin preferentially in cancer cells. Consistently, cancer patients with higher UPRER expression had generally better prognosis. Together, our study on hypothermia has led to the discovery of HSF1-UPRER in the regulation of drug sensitivity in lung cancer cells, providing novel thoughts on developing new strategies against chemoresistance.

Keywords:  HSF1; chemoresistance; hypothermia; lung cancer; unfolded protein response

DOI:  https://doi.org/10.1111/febs.16709
Int J Mol Sci. 2022 Dec 18. pii: 16162. [Epub ahead of print]23(24):

Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma.

Hideki Kosako, Yusuke Yamashita, Shuhei Morita, Sadahiro Iwabuchi, Shinichi Hashimoto, Taka-Aki Matsuoka, Takashi Sonoki, Shinobu Tamura.

  Endoplasmic reticulum stress activates inositol-requiring enzyme 1α (IRE1α) and protein kinase, R-like endoplasmic reticulum kinase (PERK), the two principal regulators of the unfolded protein response (UPR). In multiple myeloma, adaptive IRE1α signaling is predominantly activated and regulates cell fate along with PERK. Recently, we demonstrated that GNF-2, an allosteric c-Abl inhibitor, rheostatically enhanced IRE1α activity and induced apoptosis through c-Abl conformational changes in pancreatic β cells. Herein, we analyzed whether the pharmacological modulation of c-Abl conformation resulted in anti-myeloma effects. First, we investigated the effects of GNF-2 on IRE1α activity and cell fate, followed by an investigation of the anti-myeloma effects of asciminib, a new allosteric c-Abl inhibitor. Finally, we performed RNA sequencing to characterize the signaling profiles of asciminib. We observed that both GNF-2 and asciminib decreased cell viability and induced XBP1 mRNA splicing in primary human myeloma cells and myeloma cell lines. RNA sequencing identified the induction of UPR- and apoptosis-related genes by asciminib. Asciminib re-localized c-Abl to the endoplasmic reticulum, and its combination with a specific IRE1α inhibitor, KIRA8, enhanced cell death with the reciprocal induction of CHOP mRNA expression. Together, the allosteric inhibition of c-Abl-activated UPR with anti-myeloma effects; this could be a novel therapeutic target for multiple myeloma.

Keywords:  GNF-2; IRE1α; asciminib; c-Abl; multiple myeloma; unfolded protein response

DOI:  https://doi.org/10.3390/ijms232416162
Apoptosis. 2022 Dec 19.

The unfolded protein response (UPR) pathway: the unsung hero in breast cancer management.

Arunita Patra, Arghya Adhikary, Swatilekha Ghosh.

  Tumor cells always have the need to produce an increased amount of proteins in the cells. This elevated amount of proteins increases the pressure on the organelles of the cell such as the endoplasmic reticulum and compels it to increase its protein folding efficiency. However, it is by a matter of fact, that the amount of proteins synthesized outweighs the protein folding capacity of the ER which in turn switches on the UPR pathway by activating the three major molecular sensors and other signaling cascades, which helps in cell survival instead of instant death. However, if this pathway is active for a prolonged period of time the tumor cells heads toward apoptosis. Again, interestingly this is not the same as in case of non- tumorogenic cells. This exhibit a straight natural pathway for tumor cells-specific destruction which has a great implication in today's world where hormone therapies and chemo-therapies are non-effective for various types of breast cancer, a major type being Triple Negative Breast Cancer. Thus a detailed elucidation of the molecular involvement of the UPR pathway in breast cancer may open new avenues for management and attract novel chemotherapeutic targets providing better hopes to patients worldwide.

Keywords:  Apoptosis; Breast cancer; ER Stress; GRP78; UPR sensors

DOI:  https://doi.org/10.1007/s10495-022-01803-3
BMC Cancer. 2022 Dec 21. 22(1): 1338

HERPUD1 promotes ovarian cancer cell survival by sustaining autophagy and inhibit apoptosis via PI3K/AKT/mTOR and p38 MAPK signaling pathways.

Xin Nie, Dawo Liu, Mingjun Zheng, Xiao Li, Ouxuan Liu, Qian Guo, Liancheng Zhu, Bei Lin.

  HERPUD1 is an important early marker of endoplasmic reticulum stress (ERS) and is involved in the ubiquitination and degradation of several unfolded proteins. However, its role in tumorigenesis is seldom studied, and its role in ovarian cancer is unclear. Lewis y antigen is a tumor-associated sugar antigen that acts as an 'antenna' on the cell surface to receive signals from both inside and outside the cell. We previously reported that Lewis y can promote ovarian cancer by promoting autophagy and inhibiting apoptosis. In this study, we detect the expression of HERPUD1 and Lewis y antigens in 119 different ovarian cancer tissues, determine their relationship with clinicopathological parameters, analyze the correlation between these two proteins, and explore the related cancer-promoting mechanisms through MTT, flow cytometry, western blotting, and bioinformatics. HERPUD1 is highly expressed in ovarian cancer, especially in the early stage, and the expression of HERPUD1 and Lewis y antigen was positively correlated. After overexpression of Lewis y antigen, the expression level of HERPUD1 increased. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) analysis showed that HERPUD1 and its related genes are enriched in regulating immunity, endoplasmic reticulum stress, ubiquitin-dependent degradation, ERS-induced apoptosis, and other key signaling pathways. We also clarified the HERPUD1 network of kinases, microRNA and transcription factor targets, and the impact of HERPUD1 mutations on prognosis. In addition, HERPUD1 promotes the proliferation of ovarian cancer cells, inhibits apoptosis, affects the cell cycle, promotes the occurrence of autophagy, and inhibits EMT and PI3K/AKT/mTOR and p38MAPK pathways. Overall, HERPUD1, regulated by the expression of tumor-associated protein Lewis y, promotes cell survival in the early stages of tumors, suggesting that HERPUD1 may play an important role in the development of ovarian cancer.

Keywords:  Endoplasmic reticulum stress; HERPUD1; MAPK; Ovarian cancer; PI3K

DOI:  https://doi.org/10.1186/s12885-022-10248-5
J Exp Clin Cancer Res. 2022 Dec 20. 41(1): 354

LINC00629 protects osteosarcoma cell from ER stress-induced apoptosis and facilitates tumour progression by elevating KLF4 stability.

Yuan Wang, Shuo Zheng, Jian Han, Na Li, Renchen Ji, Xiaodong Li, Chuanchun Han, Wenzhi Zhao, Lu Zhang.

  BACKGROUND: Escaping from ER stress-induced apoptosis plays an important role in the progression of many tumours. However, its molecular mechanism in osteosarcoma remains incompletely understood.METHODS: The molecular mechanism was investigated using RNA sequencing, qRT-PCR and Western blot assays. The relationship between LINC00629 and KLF4 was investigated using RNA pulldown and ubiquitylation assays. The transcriptional regulation of laminin subunit alpha 4 (LAMA4) by KLF4 was identified using bioinformatic analysis, a luciferase assay, and a chromatin immunoprecipitation assay.
RESULTS: Here, we demonstrated that LINC00629 was increased under ER stress treatment. Elevated LINC00629 inhibited ER stress-induced osteosarcoma cell apoptosis and promoted clonogenicity and migration in vitro and in vivo. Further mechanistic studies indicated that LINC00629 interacted with KLF4 and suppressed its degradation, which led to a KLF4 increase in osteosarcoma. In addition, we also found that KLF4 upregulated LAMA4 expression by directly binding to its promoter and that LINC00629 inhibited ER stress-induced apoptosis and facilitated osteosarcoma cell clonogenicity and metastasis by activating the KLF4-LAMA4 pathway.
CONCLUSION: Collectively, our data indicate that LINC00629 is a critical long noncoding RNA (lncRNA) induced by ER stress and plays an oncogenic role in osteosarcoma cell by activating the KLF4-LAMA4 axis.

Keywords:  KLF4; LAMA4; LINC00629; Osteosarcoma

DOI:  https://doi.org/10.1186/s13046-022-02569-x