bims-istrec 2022-10-23 papers

bims-istrec

Biomed News

on Integrated stress response in cancer

Issue of 2022‒10‒23
five papers selected by
the Vincenzo Ciminale lab
Istituto Oncologico Veneto

Inducement of ER Stress by PAD Inhibitor BB-Cl-Amidine to Effectively Kill AML Cells.
Endoplasmic reticulum stress in melanoma pathogenesis and resistance.
A Composite Bioinformatic Analysis to Explore Endoplasmic Reticulum Stress-Related Prognostic Marker and Potential Pathogenic Mechanisms in Glioma by Integrating Multiomics Data.
Novel combretastatin A-4 derivative containing aminophosphonates as dual inhibitors of tubulin and matrix metalloproteinases for lung cancer treatment.
Depletion and Reversal of Hepatocellular Carcinoma Inducing CTL through ER Stress-Dependent PERK-CHOP Signaling Pathway.

Curr Med Sci. 2022 Oct 17.

Inducement of ER Stress by PAD Inhibitor BB-Cl-Amidine to Effectively Kill AML Cells.

Yan-Ni Sun, Yan-Ni Ma, Xiao-Qing Jia, Qi Yao, Jie-Ping Chen, Hui Li.

  OBJECTIVE: Acute myeloid leukemia (AML) is a highly heterogeneous and recurrent hematological malignancy. Despite the emergence of novel chemotherapy drugs, AML patients' complete remission (CR) remains unsatisfactory. Consequently, it is imperative to discover new therapeutic targets or medications to treat AML. Such epigenetic changes like DNA methylation and histone modification play vital roles in AML. Peptidylarginine deminase (PAD) is a protein family of histone demethylases, among which the PAD2 and PAD4 expression have been demonstrated to be elevated in AML patients, thus suggesting a potential role of PADs in the development or maintenance of AML and the potential for the identification of novel therapeutic targets.METHODS: AML cells were treated in vitro with the pan-PAD inhibitor BB-Cl-Amidine (BB-Cl-A). The AML cell lines were effectively induced into apoptosis by BB-Cl-A. However, the PAD4-specific inhibitor GSK484 did not.
RESULTS: PAD2 played a significant role in AML. Furthermore, we found that BB-Cl-A could activate the endoplasmic reticulum (ER) stress response, as evidenced by an increase in phosphorylated PERK (p-PERK) and eIF2α (p-eIF2α). As a result of the ER stress activation, the BB-Cl-A effectively induced apoptosis in the AML cells.
CONCLUSION: Our findings indicated that PAD2 plays a role in ER homeostasis maintenance and apoptosis prevention. Therefore, targeting PAD2 with BB-Cl-A could represent a novel therapeutic strategy for treating AML.

Keywords:  BB-Cl-Amidine; acute myeloid leukemia; apoptosis; endoplasmic reticulum stress; peptidylarginine deminase

DOI:  https://doi.org/10.1007/s11596-022-2637-x
Biomed Pharmacother. 2022 Nov;pii: S0753-3322(22)01130-1. [Epub ahead of print]155 113741

Endoplasmic reticulum stress in melanoma pathogenesis and resistance.

Yi Kong, Jian Jiang, Yuqiong Huang, Li Li, Xin Liu, Zilin Jin, Fen Wei, Xinxin Liu, Song Zhang, Xiaoru Duan, Yonghui Zhang, Qingyi Tong, Hongxiang Chen.

  Melanoma is the most lethal skin cancer with rising incidence worldwide. Despite significant advances in target therapy and immunotherapy, low response rates and the development of drug resistance remain key clinical barriers affecting patient prognosis. The complex interplay between multiple signaling molecules and pathways has brought little understanding of melanoma pathogenesis and resistance. The genetic mutation and hypermetabolic environment of melanoma cells lead to increasing demands for protein synthesis and perturb proteostasis resulting in endoplasmic reticulum (ER) stress. Subsequently, three unfolded protein response (UPR) signaling branches, represented by IRE1α, PERK and ATF6, are activated to direct cell fate towards pro-survival or pro-apoptosis depending on the intensity and duration of ER stress. In this review, we summarize ER stress and UPR in melanoma cells and tumor-infiltrating immune cells along with the crosstalk among these pathways. We provide the latest advances in understanding melanoma pathogenesis and resistance and discuss the potential of targeting the ER stress or UPR process for melanoma therapy.

Keywords:  ATF6; ER stress; IRE1; Melanoma; PERK; UPR

DOI:  https://doi.org/10.1016/j.biopha.2022.113741
J Oncol. 2022 ;2022 9886044

A Composite Bioinformatic Analysis to Explore Endoplasmic Reticulum Stress-Related Prognostic Marker and Potential Pathogenic Mechanisms in Glioma by Integrating Multiomics Data.

Xin Fan, Xiyi Nie, Junwen Huang, Lingling Zhang, Xifu Wang, Min Lu.

In recent years, abnormal endoplasmic reticulum stress (ERS) response, as an important regulator of immunity, may play a vital role in the occurrence, development, and treatment of glioma. Weighted correlation network analysis (WGCNA) based on six glioma datasets was used to screen eight prognostic-related differentially expressed ERS-related genes (PR-DE-ERSGs) and to construct a prognostic model. BMP2 and HEY2 were identified as protective factors (HR < 1), and NUP107, DRAM1, F2R, PXDN, RNF19A, and SCG5 were identified as risk factors for glioma (HR > 1). QRT-PCR further supported significantly higher DRAM1 and lower SCG5 relative mRNA expression in gliomas. Our model has demonstrated excellent performance in predicting the prognosis of glioma patients from numerous datasets. In addition, the model shows good stability in multiple tests. Our model also shows broad clinical promise in predicting drug treatment effects. More immune cells/processes in the high-risk population with poor prognosis illustrate the importance of the tumor immunosuppressive environment in glioma. The potential role of the HEY2-based competitive endogenous RNA (ceRNA) regulatory network in glioma was validated and revealed the possible important role of glycolysis in glioma ERS. IDH1 and TP53 mutations with better prognosis were strongly associated with the risk score and PR-DE-ERSGs expression in the model. mDNAsi was also closely related to the risk score and clinical characteristics.

DOI: https://doi.org/10.1155/2022/9886044
Eur J Med Chem. 2022 Oct 04. pii: S0223-5234(22)00719-X. [Epub ahead of print]244 114817

Novel combretastatin A-4 derivative containing aminophosphonates as dual inhibitors of tubulin and matrix metalloproteinases for lung cancer treatment.

Xiaochao Huang, Yuanhang Chen, Wentian Zhong, Zhikun Liu, Haijiang Zhang, Bin Zhang, Hengshan Wang.

  Here, sixteen novel conjugates containing tubulin inhibitor and matrix metalloproteinase inhibitor was synthesized together with their activity evaluated. Among them, 9e exhibited the most potent activity against various human cancer cells (IC50 values was 0.19-0.42 μM) as well as multidrug-resistant tumor cells (A549/CDDP and MCF-7/DOX) and also showed significantly lower cytotoxic activity toward human normal liver cells LO2 in comparison with that of CA-4. Interestingly, 9e not only strongly inhibited tubulin polymerization, and induced cell apoptosis and cell cycle arrest in G2/M stage, but also remarkably displayed inhibition of cell migration against A549 cells in vitro, and exhibited a moderate activity toward MMP-2, MMP-3 and MMP-9, respectively. Moreover, the significant down-regulation in the levels of Bcl-2 protein and up-regulated levels of proteins, such as Bax, p53 and caspase-3, indicated that 9e can induce apoptosis via mitochondria-dependent apoptosis pathway. Additionally, 9e can also cause ER stress demonstrating as up-regulation express of proteins (CHOP, p-eIF2a, and p-PERK). Importantly, 9e displayed significant in vivo antitumor efficacy in A549 xenograft models without inducing apparent systemic toxicity. Collectively, this work indicated that compound 9e, a dual MMPs and tubulin inhibitor, is a novel and promising agent for cancer therapy.

Keywords:  Aminophosphonate; Apoptosis; CA-4; Dual inhibitor; MMPs; Tubulin

DOI:  https://doi.org/10.1016/j.ejmech.2022.114817
Can J Gastroenterol Hepatol. 2022 ;2022 6413783

Depletion and Reversal of Hepatocellular Carcinoma Inducing CTL through ER Stress-Dependent PERK-CHOP Signaling Pathway.

Mengnan Guo, Wei Wang, Wen Bai, Zekun Bai, Weixi Chen, Yali Su, Jinghua Wu.

Aims: In this report, it was investigated that hepatoma cells can cause downregulation of cytotoxic T lymphocyte (CTL) function and tea polyphenols (TPs) can reverse downregulation of CTL function.Methods: The expression of GRP78, PD-1, and TIM-3 was detected by western blotting in CTLL-2 cocultured with Hepa1-6 cells. Moreover, perforin (PRF1) and granzyme B (GzmB) protein levels and ER morphology were examined by ELISA and TEM, respectively. After 4-phenylbutyric acid (4-PBA) or tunicamycin (TM) treatment, programmed cell death protein 1 (PD-1), and mucin domain 3 (TIM-3), PRF1, and GzmB were measured by western blotting and ELISA. After sh-CHOP or GSK2656157 (PERK inhibitor) stimulation, the activation of the PERK-CHOP pathway was detected in CTLL-2 cells. Finally, changes in PD-1, TIM-3, PRF1, and GzmB levels were detected to verify the reversal of CTL depletion by TP.
Results: The expression of GRP78, PD-1, and TIM-3 clearly increased, and swelling was observed for the endoplasmic reticulum (ER) in CTLL-2 cells cocultured with hepatoma cells. Concurrently, the levels of PRF1 and GzmB decreased. CTLL-2 depletion was induced after stimulation with TM and differed from 4-PBA stimulation. Treatment with sh-CHOP or GSK2656157 caused a decrease in PD-1 and TIM-3 expression, whereas the expression of PRF1 and GzmB clearly increased. After adding TP, the function of CTLs increased markedly.
Conclusion: Hepatoma cells induced the depletion of CTLs through the ER stress PERK-CHOP pathway, and TP reversed this depletion by downregulating ER stress.

DOI: https://doi.org/10.1155/2022/6413783