bims-istrec Biomed News
on Integrated stress response in cancer
Issue of 2022‒06‒19
eight papers selected by
Vincenzo Ciminale’s Lab
Istituto Oncologico Veneto

  1. Front Oncol. 2022 ;12 911615
      We recently reported that carnosol induces ROS-dependent autophagy and apoptosis in breast cancer cells. We also reported that carnosol inhibits breast cancer cell migration, invasion, and in ovo tumor growth, as well as targets STAT3, PCAF, and p300 to proteasome degradation. Here, we investigated the molecular mechanisms underlying its anti-malignant activity in breast cancer. We report that carnosol induces a ROS-dependent type I and type II programmed cell death (PCD-I or PCD-II, respectively), which occurred independently of each other. Indeed, chemical inhibition of autophagy had no effect on the induction of apoptosis, evident by the absence of cleaved PARP. Electron microscopy revealed that carnosol-treated cells exhibited enlarged endoplasmic reticulum, characteristic of ER stress. Markers of the three unfolded protein response pathways (PERK, IRE-1 α, and ATF6), namely ATF4, CHOP, phospho-IRE-1α, XBP1S, and cleaved ATF6 were upregulated in a ROS-dependent manner. In addition, carnosol induced a ROS-dependent activation of p38MAPK, increased the overall level of protein polyubiquitination, and targeted mTOR protein to proteasome degradation. Interestingly, inhibition of p38MAPK, by SB202190 and 203580, reduced cell death, selectively blocked the induction of IRE-1α and ATF6 UPR sensors and inhibited autophagy. In addition, inhibition of p38 reduced the carnosol-induced polyubiquitination and rescued mTOR, PCAF, and STAT3 from proteasomal degradation. Importantly, activation of PERK sensors and induction of apoptosis occurred independently of p38 activation. Taken together, our results suggest that ROS-dependent induced-ER stress contributes to carnosol-induced apoptotic and autophagic cell death in breast cancer cells, and further confirm that carnosol is a promising agent for breast cancer therapy.
    Keywords:  ER stress; ROS; autophagy; breast cancer; p38MAPK; proteasome; unfolded protein response
  2. J Immunol Res. 2022 ;2022 1917585
      Objective: Gastric cancer is a prevalent malignant tumor with high morbidity and poor prognosis. Asiaticoside (AC) has antitumor effects, while its role in gastric cancer is elusive. Thus, this study investigated the effect of AC on gastric cancer progression.Methods: Cell viability and migration were determined using the CCK-8 and Transwell migration assay. Endoplasmic reticulum stress was detected through measuring the expressions of GRP78, Chop, and hnRNPA1 by Western blot. The luciferase assay confirmed the relationship between miR-635 and High Mobility Group AT-Hook 1 (HMGA1). The effect of AC on tumor growth was evaluated by establishing a xenograft tumor. The survival rate of mice was analyzed by Kaplan-Meier analysis.
    Results: AC suppressed gastric cancer cell viability and restrained cell migration. AC inhibited the expressions of the cell proliferation marker PCNA and EMT-related marker N-cadherin and increased E-cadherin expression. AC elevated the levels of GRP78 and Chop and suppressed the level of hnRNPA1. In addition, AC restrained gastric cancer proliferation and migration ability and induced endoplasmic reticulum stress by upregulating miR-635 expression. Furthermore, HMGA1 was proven to be a target of miR-635. AC constrained gastric cancer cell proliferation and migration and promoted endoplasmic reticulum stress by regulating HMGA1. Moreover, AC suppressed in vivo tumor growth and improved the survival time of mice. Additionally, AC elevated the expressions of miR-635, E-cadherin, GRP78, and Chop and inhibited Ki-67, HMGA1, N-cadherin, and hnRNPA1 expressions in tumor tissues of mice.
    Conclusion: AC suppressed gastric cancer progression and induced endoplasmic reticulum stress via the miR-635/HMGA1 axis, providing a valuable drug against gastric cancer.
  3. Front Genet. 2022 ;13 850200
      Liver cancer is the sixth most frequently diagnosed primary malignancy and ranks as the third leading cause of cancer-related death worldwide in 2020. ER stress also plays a vital role in the pathogenesis of malignancies. In the current study, we aimed to construct an endoplasmic reticulum stress-related genes (ERGs) signature to predict the overall survival (OS) of patients with HCC. Differentially expressed ERGs (DE-ERGs) were analyzed using The Cancer Genome Atlas (TCGA-LIHC cohort) and International Cancer Genome Consortium (ICGC-LIRI-JP cohort) databases. The prognostic gene signature was identified by the univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO)-penalized Cox proportional hazards regression analysis. The predictive ability of the model was evaluated by utilizing Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves. Gene set variant analysis (GSVA) was performed to explore the underlying biological processes and signaling pathways. CIBERPORT and single-sample Gene Set Enrichment Analysis (ssGSEA) were implemented to estimate the immune status between the different risk groups. A total of 113 DE-ERGs were identified between 50 normal samples and 365 HCC samples in the TCGA-LIHC cohort, and 48 DE-ERGs were associated with OS through the univariate Cox regression. A six DE-ERGs (PPARGC1A, SQSTM1, SGK1, PON1, CDK1, and G6PD) signature was constructed and classified patients into high-risk and low-risk groups. The risk score was an independent prognostic indicator for OS (HR > 1, p < 0.001). The function enrichment analysis indicated that cell cycle, RNA degradation, protein localization, and cell division were the main biological processes. The high-risk group had higher immune cell infiltration levels than those of the low-risk group. We predicted the response to targeted therapy in high- and low-risk patients with HCC and found that the high-risk patients were more sensitive to pazopanib. At last, we verified the expression of the six gene patterns in HCC tissues by qRT-PCR and immunohistochemistry. This signature may be a potential tool to provide a choice for prognosis prediction and personal management of patients with HCC.
    Keywords:  endoplasmic reticulum stress; gene signature; hepatocellular cancer; immune infiltrate cells; overall survival
  4. Am J Cancer Res. 2022 ;12(5): 2277-2292
      Endoplasmic reticulum (ER) stress occurs when proteins are affected by various factors, fail to fold properly into higher structures and accumulate in the lumen of the ER, which activates the unfolded protein response (UPR) to restore normal cellular function or induce apoptosis as a self-protective mechanism. However, a growing number of studies have shown that the three branches of ER stress and the UPR can mediate inflammation and cancer development by interacting with inflammatory transformation-related signaling pathways. Targeting the UPR, especially the use of small molecules that target the active sites of the enzymes IRE1α and PERK and BIP/GRP78 inhibitors are potential strategies for treating tumors and have shown promising results in some tumor models. Therefore, in this review, we summarize the progress of ER stress/UPR research and the signaling pathways associated with inflammatory cancer transformation, provide an in-depth description of the mechanisms of these pathways, and outline strategies in the field of UPR biology in tumor therapy to provide new ideas for the mechanisms of inflammatory cancer transformation and tumor-related treatment.
    Keywords:  ER stress; inflammatory cancer transformation; targeted therapy; unfolded protein response
  5. Research (Wash D C). 2022 ;2022 9814652
      Despite recent advances in the management and treatment of esophageal squamous cell carcinoma (ESCC), the prognosis remains extremely poor, and current nonsurgical treatment options are limited. To identify new therapeutic targets, we screened a curated library of epigenetic compounds using a panel of cancer cell lines and found that coinhibiting the histone demethylase LSD1 and the histone methyltransferase G9a potently suppresses cell growth; similar results were obtained by knocking down both LSD1 and G9a expression. Importantly, we also found that inhibiting LSD1 and G9a significantly decreased tumor growth in a xenograft mouse model with ESCC cell lines. To examine the clinical relevance of these findings, we performed immunohistochemical analyses of microarray profiling data obtained from human esophageal squamous cancer tissues and found that both LSD1 and G9a are upregulated in cancer tissues compared to healthy tissues, and this increased expression was significantly correlated with poor prognosis. Mechanistically, we discovered that inhibiting LSD1 and G9a induces cell death via S-phase arrest and apoptosis, and cotargeting ER stress pathways increased this effect both in vitro and in vivo. Taken together, these findings provide compelling evidence that targeting LSD1, G9a, and ER stress-related pathways may serve as a viable therapeutic strategy for ESCC.
  6. Cell Death Discov. 2022 Jun 11. 8(1): 286
      2-Deoxyglucose (2-DG) can be used in antitumour research by inhibiting glycolysis and promoting the endoplasmic reticulum stress (ERS) pathway, but its clinical application is restricted due to dose-limiting side effects and survival chance for cancer cells by protective autophagy. Therefore, our research explored whether the combination of hydroxychloroquine (HCQ), an FDA-approved autophagy inhibiting drug, and 2-DG is a promising therapeutic strategy. Here, we report that HCQ combined with 2-DG can further inhibit the viability and migration and induce apoptosis of breast tumour cells compared with other individual drugs. The combination of 2-DG and HCQ can significantly reduce transplanted tumour size and tumour cell metastasis of the lung and liver in vivo. At the cellular level, HCQ suppressed autolysosome formation and terminated the autophagy process induced by 2-DG-mediated ERS, resulting in the continuous accumulation of misfolded proteins in the endoplasmic reticulum, which generated sustained ERS through the PERK-eIF2α-ATF-4-CHOP axis and triggered the transformation from a survival process to cell death. Our research reinforced the research interest of metabolic disruptors in triple-negative breast cancer and emphasized the potential of the combination of 2-DG and HCQ as an anticancerous treatment.
  7. Mol Ther Nucleic Acids. 2022 Jun 14. 28 877-891
      Advances in gene therapy research have resulted in the successful development of new therapies for clinical use. Here, we explored a gene targeting approach to deplete ephrinB2 from colorectal cancer cells using an inducible lentiviral vector. EphrinB2, a transmembrane ephrin ligand, promotes colorectal cancer cell growth and viability and predicts poor patient survival when expressed at high levels in colorectal cancer tissues. We discovered that lentiviral vector integration and expression in the host DNA frequently drive divergent host gene transcription, generating antisense reads coupled with splicing events and generation of chimeric vector/host transcripts. Antisense transcription of host DNA was linked to development of an integrated stress response and cell death. Despite recent successes, off-target effects remain a concern in genetic medicine. Our results provide evidence that divergent gene transcription is a previously unrecognized off-target effect of lentiviral vector integration with built-in properties for regulation of gene expression.
    Keywords:  MT: Oligonucleotides; Therapies and Applications; antisense reads; colorectal cancer; ephrinB2; gene therapy; integrated stress response; lentiviral vector; shRNA; vector integration
  8. J Cell Sci. 2022 Jun 17. pii: jcs.259629. [Epub ahead of print]
      Stress granules (SGs) can assemble in cancer cells upon chemotoxic stress. Glucocorticoids function during stress responses and are administered with chemotherapies. The roles of glucocorticoids in SG assembly and disassembly pathways are unknown. We examined whether combining glucocorticoids such as cortisone with chemotherapies from the vinca-alkaloid family that dismantle the microtubule network, will affect SG assembly and disassembly pathways and influence cell viability in cancer cells and in human-derived organoids. Cortisone augmented SG formation when combined with Vinorelbine (VRB). Live-cell imaging showed that cortisone increased SG assembly rates but reduced SG clearance rates after stress, by increasing protein residence times within the SGs. Mechanistically, VRB and cortisone signaled through the eIF2α-mediated integrated stress response yet induced different kinases, with cortisone activating the GCN2 kinase. Cortisone increased VRB-induced cell death and reduced the population of cells trapped in mitotic catastrophe. These effects were mediated by G3BP1/2 core SG proteins. In conclusion, glucocorticoids induce SG assembly and cell death when administered with chemotherapies, suggesting that combining glucocorticoids with chemotherapies can enhance cancer cell chemosensitivity.
    Keywords:  FRAP; Live-cell imaging; Stress; Stress granules