bims-istrec 2022-10-09 papers

bims-istrec

Biomed News

on Integrated stress response in cancer

Issue of 2022‒10‒09
eight papers selected by
the Vincenzo Ciminale lab
Istituto Oncologico Veneto

Prognosis and immune infiltration analysis of endoplasmic reticulum stress-related genes in bladder urothelial carcinoma.
Melittin induces ferroptosis and ER stress-CHOP-mediated apoptosis in A549 cells.
Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids.
Echinatin induces reactive oxygen species-mediated apoptosis via JNK/p38 MAPK signaling pathway in colorectal cancer cells.
Suppression of endoplasmic reticulum stress-dependent autophagy enhances cynaropicrin-induced apoptosis via attenuation of the P62/Keap1/Nrf2 pathways in neuroblastoma.
Inhibition of Ca2+ entry by capsazepine analog CIDD-99 prevents oral squamous carcinoma cell proliferation.
Injectable versatile liquid-solid transformation implants alliance checkpoint blockade for magnetothermal dynamic-immunotherapy.
Unfolded protein response at the cross roads of tumourigenesis, oxygen sensing and drug resistance in clear cell renal cell carcinoma.

Front Genet. 2022 ;13 965100

Prognosis and immune infiltration analysis of endoplasmic reticulum stress-related genes in bladder urothelial carcinoma.

Yaxuan Wang, Haixia Zhu, Xiaolin Wang.

  Background: Abnormal activation of endoplasmic reticulum (ER) stress sensors and their downstream signalling pathways is a key regulator of tumour growth, tumour metastasis and the response to chemotherapy, targeted therapy and immunotherapy. However, the study of ER stress on the immune microenvironment of bladder urothelial carcinoma (BLCA) is still insufficient. Methods: Firstly, 23 ER stress genes were selected to analyse their expression differences and prognostic value in BLCA based on the existing BLCA genome atlas data. According to the expression level of ER stress-related genes in BLCA, two independent clusters were identified using consensus cluster analysis. Subsequently, the correlation between these two clusters in terms of the immune microenvironment and their prognostic value was analysed. Finally, we analysed the prognostic value of the key ER stress gene HSP90B1 in BLCA and its corresponding mechanism that affects the immune microenvironment. Results: Consensus clustering showed a worse prognosis and higher expression of immunoassay site-related genes (HAVCR2, PDCD1, CTLA4, CD274, LAG3, TIGIT and PDCD1LG2) in cluster 1 compared with cluster 2. Additionally, both TIMER and CIBERSORT algorithms showed that the expression of immune infiltrating cells in cluster 1 was significantly higher than that in cluster 2. Subsequently, HSP90B1 was identified as a key ER stress gene in BLCA, and its high expression indicated poor prognosis and was closely related to PD1. We also analysed the correlation between HSP90B1 expression and immune-infiltrating cell related biomarkers, which showed positive results. Finally, we verified the prognostic value of HSP90B1 in BLCA using an immunohistochemical assay in a tissue microarray of 100 patients with BLCA, validating the potential of HSP90B1 as a prognostic biomarker in patients with BLCA. Conclusion: Our work reveals that ER stress genes play a crucial role in the BLCA immunological milieu, and HSP90B1 is a potential prognostic biomarker and therapeutic target for cancer immunotherapy.

Keywords:  BLCA; ER stress; HSP90B1; immune infiltration; therapeutic target

DOI:  https://doi.org/10.3389/fgene.2022.965100
Free Radic Res. 2022 Oct 04. 1-26

Melittin induces ferroptosis and ER stress-CHOP-mediated apoptosis in A549 cells.

Xuan Li, Sen Zhu, Zheng Li, Yuqi Meng, Sujie Huang, Qiyao Yu, Bin Li.

  Melittin is a natural polypeptide present in bee venom, with significant anti-tumor activity. Melittin has been reported to induce cell death in lung carcinoma cell line A549 cells, suggesting an excellent potential for treating lung cancer. However, the core mechanism underlying melittin-induced cell death in A549 cells remains unclear. This work reports that melittin induces reactive oxygen species (ROS) burst, upregulates intracellular Fe2+ levels, disrupts the glutathione-glutathione peroxidase 4 antioxidant system, and increases lipid peroxide accumulation, eventually inducing cell death, indicating that ferroptosis may be involved in the antitumor effects of melittin in A549 cells. Furthermore, A549 cells treated with the ferroptosis inhibitors ferrostatin-1 and deferoxamine demonstrated that these inhibitors could reverse the cell death induced by melittin, further confirming that melittin induces A549 cell death via ferroptosis. Furthermore, the results also illustrated that melittin activated the endoplasmic reticulum (ER) stress-CHOP (C/EBP homologous protein) apoptotic signal, closely associated with high-level intracellular ROS. The ER stress inhibitor, 4-Phenyl butyric acid, was used to confirm that ER stress-CHOP apoptotic signaling is another molecular mechanism of melittin-induced A549 cell death. Thus, our results demonstrate that ferroptosis and ER stress-CHOP signaling are key molecular mechanisms of melittin-induced cell death in lung cancer.Key policy highlightsMelittin upregulates intracellular Fe2+ levels, leading to the accumulation of lipid peroxides in A549 cells.Melittin disrupts the glutathione-glutathione peroxidase 4 antioxidant system in A549 cells.Melittin induces activation of endoplasmic reticulum stress-C/EBP homologous protein apoptosis signal.Ferroptosis and ER stress are the core molecular mechanisms underlying melittin-induced apoptosis in A549 cells.

Keywords:  A549 cells; ER stress; Ferroptosis; melittin; reactive oxygen species (ROS)

DOI:  https://doi.org/10.1080/10715762.2022.2131551
Proc Natl Acad Sci U S A. 2022 Oct 11. 119(41): e2203480119

Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids.

Guangyuan Zhao, Yuying Tan, Horacio Cardenas, David Vayngart, Yinu Wang, Hao Huang, Russell Keathley, Jian-Jun Wei, Christina R Ferreira, Sandra Orsulic, Ji-Xin Cheng, Daniela Matei.

  Fatty acids are an important source of energy and a key component of phospholipids in membranes and organelles. Saturated fatty acids (SFAs) are converted into unsaturated fatty acids (UFAs) by stearoyl Co-A desaturase (SCD), an enzyme active in cancer. Here, we studied how the dynamics between SFAs and UFAs regulated by SCD impacts ovarian cancer cell survival and tumor progression. SCD depletion or inhibition caused lower levels of UFAs vs. SFAs and altered fatty acyl chain plasticity, as demonstrated by lipidomics and stimulated Raman scattering (SRS) microscopy. Further, increased levels of SFAs resulting from SCD knockdown triggered endoplasmic reticulum (ER) stress response with brisk activation of IRE1α/XBP1 and PERK/eIF2α/ATF4 axes. Disorganized ER membrane was visualized by electron microscopy and SRS imaging in ovarian cancer cells in which SCD was knocked down. The induction of long-term mild ER stress or short-time severe ER stress by the increased levels of SFAs and loss of UFAs led to cell death. However, ER stress and apoptosis could be readily rescued by supplementation with UFAs and reequilibration of SFA/UFA levels. The effects of SCD knockdown or inhibition observed in vitro translated into suppression of intraperitoneal tumor growth in ovarian cancer xenograft models. Furthermore, a combined intervention using an SCD inhibitor and an SFA-enriched diet initiated ER stress in tumors growing in vivo and potently blocked their dissemination. In all, our data support SCD as a key regulator of the cancer cell fate under metabolic stress and point to treatment strategies targeting the lipid balance.

Keywords:  ER stress; SRS imaging; fatty acids; lipid metabolism; ovarian cancer

DOI:  https://doi.org/10.1073/pnas.2203480119
Phytother Res. 2022 Oct 02.

Echinatin induces reactive oxygen species-mediated apoptosis via JNK/p38 MAPK signaling pathway in colorectal cancer cells.

Ah-Won Kwak, Jin-Young Lee, Seung-On Lee, Ji-Hye Seo, Jin Woo Park, Yung Hyun Choi, Seung-Sik Cho, Goo Yoon, Mee-Hyun Lee, Jung-Hyun Shim.

  Colorectal cancer (CRC) is a very common and deadly cancer worldwide, and oxaliplatin is used as first-line chemotherapy. However, resistance usually develops, limiting treatment. Echinatin (Ech) is the main component of licorice and exhibits various therapeutic effects on inflammation-mediated diseases and cancer, ischemia/reperfusion, and liver injuries. The present study elucidated the underlying molecular mechanism of Ech-induced apoptosis in both oxaliplatin-sensitive (HT116 and HT29) and -resistant (HCT116-OxR and HT29-OxR) CRC cells. To evaluate the antiproliferative activities of Ech, we performed MTT and soft agar assays. Ech reduced viability, colony size, and numbers of CRC cells. The underlying molecular mechanisms were explored by various flow cytometry analyses. Ech-induced annexin-V stained cells, reactive oxygen species (ROS) generation, cell cycle arrest, JNK/p38 MAPK activation, endoplasmic reticulum (ER) stress, mitochondrial membrane potential depolarization, and multi-caspase activity. In addition apoptosis-, cell cycle-, and ER stress-related protein levels were confirmed by western blotting. Moreover, we verified ROS-mediated cell death by treatment with inhibitors such as N-acetyl-L-cysteine, SP600125, and SB203580. Taken together, Ech exhibits anticancer activity in oxaliplatin-sensitive and -resistant CRCs by inducing ROS-mediated apoptosis through the JNK/p38 MAPK signaling pathway. This is the first study to show that Ech has the potential to treat drug-resistant CRC, providing new directions for therapeutic strategies targeting drug-resistant CRC.

Keywords:  apoptosis, JNK/p38 MAPKs signaling pathway; echinatin; oxaliplatin-resistant colon cancer; reactive oxygen species

DOI:  https://doi.org/10.1002/ptr.7634
Front Pharmacol. 2022 ;13 977622

Suppression of endoplasmic reticulum stress-dependent autophagy enhances cynaropicrin-induced apoptosis via attenuation of the P62/Keap1/Nrf2 pathways in neuroblastoma.

Randong Yang, Shurong Ma, Ran Zhuo, Lingqi Xu, Siqi Jia, Pengcheng Yang, Ye Yao, Haibo Cao, Liya Ma, Jian Pan, Jian Wang.

  Autophagy has dual roles in cancer, resulting in cellular adaptation to promote either cell survival or cell death. Modulating autophagy can enhance the cytotoxicity of many chemotherapeutic and targeted drugs and is increasingly considered to be a promising cancer treatment approach. Cynaropicrin (CYN) is a natural compound that was isolated from an edible plant (artichoke). Previous studies have shown that CYN exhibits antitumor effects in several cancer cell lines. However, it anticancer effects against neuroblastoma (NB) and the underlying mechanisms have not yet been investigated. More specifically, the regulation of autophagy in NB cells by CYN has never been reported before. In this study, we demonstrated that CYN induced apoptosis and protective autophagy. Further mechanistic studies suggested that ER stress-induced autophagy inhibited apoptosis by activating the p62/Keap1/Nrf2 pathways. Finally, in vivo data showed that CYN inhibited tumour growth in xenografted nude mice. Overall, our findings suggested that CYN may be a promising candidate for the treatment of NB, and the combination of pharmacological inhibitors of autophagy may hold novel therapeutic potential for the treatment of NB. Our paper will contribute to the rational utility and pharmacological studies of CYN in future anticancer research.

Keywords:  apoptosis; autophagy; cynaropicrin; neuroblastoma; p62/Keap1/Nrf2

DOI:  https://doi.org/10.3389/fphar.2022.977622
Front Physiol. 2022 ;13 969000

Inhibition of Ca2+ entry by capsazepine analog CIDD-99 prevents oral squamous carcinoma cell proliferation.

Yuyang Sun, Emily K Zboril, Jorge J De La Chapa, Xiufang Chai, Viviane Nascimento Da Conceicao, Matthew C Valdez, Stanton F McHardy, Cara B Gonzales, Brij B Singh.

  Oral cancer patients have a poor prognosis, with approximately 66% of patients surviving 5-years after diagnosis. Treatments for oral cancer are limited and have many adverse side effects; thus, further studies are needed to develop drugs that are more efficacious. To achieve this objective, we developed CIDD-99, which produces cytotoxic effects in multiple oral squamous cell carcinoma (OSCC) cell lines. While we demonstrated that CIDD-99 induces ER stress and apoptosis in OSCC, the mechanism was unclear. Investigation of the Bcl-family of proteins showed that OSCC cells treated with CIDD-99 undergo downregulation of Bcl-XL and Bcl-2 anti-apoptotic proteins and upregulation of Bax (pro-apoptotic). Importantly, OSCC cells treated with CIDD-99 displayed decreased calcium signaling in a dose and time-dependent manner, suggesting that blockage of calcium signaling is the key mechanism that induces cell death in OSCC. Indeed, CIDD-99 anti-proliferative effects were reversed by the addition of exogenous calcium. Moreover, electrophysiological properties further established that calcium entry was via the non-selective TRPC1 channel and prolonged CIDD-99 incubation inhibited STIM1 expression. CIDD-99 inhibition of calcium signaling also led to ER stress and inhibited mitochondrial complexes II and V in vitro. Taken together, these findings suggest that inhibition of TRPC mediates induction of ER stress and mitochondrial dysfunction as a part of the cellular response to CIDD-99 in OSCC.

Keywords:  Ca2+ homeostasis; ER stress; SOCE channels; TRPC1/STIM1; and oral cancer; mitochondrial dysfunction

DOI:  https://doi.org/10.3389/fphys.2022.969000
Mater Today Bio. 2022 Dec;16 100442

Injectable versatile liquid-solid transformation implants alliance checkpoint blockade for magnetothermal dynamic-immunotherapy.

Mengna Wang, Siyu Deng, Yijia Cao, Hang Zhou, Wei Wei, Kexiao Yu, Youde Cao, Bing Liang.

  The ongoing circulating energy loss, low reactive oxygen species (ROS) accumulation and poor immunogenicity of tumors make it difficult to induce sufficient immunogenic cell death (ICD) in the tumor immunosuppressive microenvironment (TIME), resulting in unsatisfactory immunotherapy efficacy. Furthermore, for highly malignant tumors, simply enhancing ICD is insufficient for exhaustively eliminating the tumor and inhibiting metastasis. Herein, we propose a unique magnetothermal-dynamic immunotherapy strategy based on liquid-solid transformation porous versatile implants (Fe3O4/AIPH@PLGA) that takes advantage of less energy loss and avoids ongoing circulating losses by minimally invasive injection into tumors. In addition, the magnetothermal effect regresses and eliminates tumors that are not limited by penetration to simultaneously trigger 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH) decomposition and generate a large amount of oxygen-irrelevant free radicals and heat shock protein (HSP) accumulation by heating, evoking both intracellular oxidative stress and endoplasmic reticulum (ER) stress to induce large-scale ICD and enhance tumor immunogenicity. More importantly, in orthotopic bilateral breast tumor models, a significant therapeutic effect was obtained after combining amplified ICD with CTLA4 checkpoint blockade. The 21-day primary and distant tumor inhibition rates reached 90%, and the underlying mechanism of the effective synergetic strategy of inducing the T-cell-related response, the immune memory effect and TIME reprogramming in vivo was verified by immune cell analyses. This remarkable therapeutic effect provides a new direction for antitumor immunotherapy based on magnetothermally controlled oxygen-independent free radical release.

Keywords:  CTLA4 checkpoint blockade; Free radicals; Immunogenic cell death; Liquid-solid transformation; Magnetothermal

DOI:  https://doi.org/10.1016/j.mtbio.2022.100442
Biochim Biophys Acta Rev Cancer. 2022 Oct 01. pii: S0304-419X(22)00139-1. [Epub ahead of print] 188814

Unfolded protein response at the cross roads of tumourigenesis, oxygen sensing and drug resistance in clear cell renal cell carcinoma.

Yew Hwang Chee, Afshin Samali, Claire M Robinson.

  Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. Despite therapeutic advances, long term survival in patients diagnosed with advanced disease is low. Efforts to understand the mechanisms promoting disease progression will likely produce novel therapeutic targets. The unfolded protein response (UPR) is activated when unfolded protein accumulates in the endoplasmic reticulum (ER) upon cellular stress. Constitutive UPR activation is a characteristic of many malignancies. We discuss the accumulating evidence that describes a role for the UPR in ccRCC. Studies focused on UPR signalling may provide compelling avenues for therapeutic intervention in the future.

Keywords:  Clear cell renal cell carcinoma (ccRCC); Tumourigenesis; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/j.bbcan.2022.188814