bims-istrec Biomed News
on Integrated stress response in cancer
Issue of 2022‒05‒22
four papers selected by
Vincenzo Ciminale’s Lab
Istituto Oncologico Veneto

  1. Bioessays. 2022 May 19. e2200026
      The integrated stress response (ISR) is a key determinant of tumorigenesis in response to oncogenic forms of stress like genotoxic, proteotoxic and metabolic stress. ISR relies on the phosphorylation of the translation initiation factor eIF2 to promote the translational and transcriptional reprogramming of gene expression in stressed cells. While ISR promotes tumor survival under stress, its hyperactivation above a level of tolerance can also cause tumor death. The tumorigenic function of ISR has been recently demonstrated for lung adenocarcinomas (LUAD) with KRAS mutations. ISR mediates the translational repression of the dual-specificity phosphatase DUSP6 to stimulate ERK activity and LUAD growth. The significance of this finding is highlighted by the strong anti-tumor responses of ISR inhibitors in pre-clinical LUAD models. Elucidation of the mechanisms of ISR action in LUAD progression via cell-autonomous and immune regulatory mechanisms will provide a better understanding of its tumorigenic role to fully exploit its therapeutic potential in the treatment of a deadly form of cancer.
    Keywords:  KRAS oncogene; cancer therapeutics; lung adenocarcinoma; mRNA translation; oncogenic stress; transgenic mouse; translation initiation factor eIF2
  2. J Food Biochem. 2022 May 21. e14221
      Human oral squamous cell carcinoma (OSCC) has been one of the most common oral cancers owing to high percentage of betel nuts chewers, smokers, and alcohol consumption. With current treatment strategies in OSCC, more than half patients relapse and develop distant metastases with poor prognosis. To overcome the incident, OSCC poses a challenge in current therapies and treatments. Naringenin, a natural flavonoid, has been noted for antitumor effects on various types of cancers; however, the effects of naringenin on OSCC remain bias. In this study, naringenin demonstrated the potential multifunction in human OSCC cells not only leading to cell apoptosis, but also alternating the general function of autophagy, serving as pro-survival mechanism by inducing the endoplasmic reticulum (ER) stress signaling through intracellular reactive oxygen species (ROS) production. In the process of programmed cell death, naringenin induced apoptotic signaling through caspase-cascade, mitochondrial dysfunction, and ER stress by aberrance of Ca2+ release. In contrast, under the presence of naringenin, the pro-survival has been altered into pro-death to activate the caspases-mediated apoptosis achieving cell death. The cross-function of apoptosis and autophagy has demonstrated the effect of naringenin-induced intracellular ROS activity in OSCC cells. Therefore, this study found that the effect of naringenin induces intracellular ROS to trigger programmed cell death and ER stress through the mechanisms of apoptosis and autophagy in human oral squamous carcinoma. PRACTICAL APPLICATIONS: This study revealed that naringenin debilitated the OSCC cell viability via the intracellular ROS production, ER stress, and autophagy, leading to cell apoptosis. Based on these studies and findings, naringenin provided an antitumor effect as a novel natural compound to improve the current therapies in OSCC.
    Keywords:  apoptosis; autophagy; human oral squamous cell carcinoma; naringenin
  3. J Immunol Res. 2022 ;2022 6567916
      Lung adenocarcinoma (LUAD) is the main pathological subtype of non-small-cell lung cancer. Endoplasmic reticulum stress (ERS) has been found to be involved in multiple tumor-related biological processes. At present, a comprehensive analysis of ERS-related genes in LUAD is still lacking. A total of 1034 samples from TCGA and GEO were used to screen differentially expressed genes. Further, Random Forest algorithm was utilized to screen characteristic genes related to prognosis. Then, LASSO Cox regression was used to construct a prognostic signature. Taking the median of signature score as the threshold, patients were separated into high-risk (HR) group and low-risk (LR) group. Tumor mutation burden (TMB), immune cell infiltration, cancer stem cell infiltration, expression of HLA, and immune checkpoints of the two risk groups were analyzed. TIDE score was used to evaluate the response of the two risk groups to immunotherapy. Finally, the gene expression was verified in clinical tissues with RT-qPCR. An eight-gene signature (ADRB2, AGER, CDKN3, GJB2, SFTPC, SLC2A1, SLC6A4, and SSR4) was constructed. TMB and cancer stem cell infiltration were higher in the HR group than the LR group. TIDE score and expression level of HLA were higher in the LR group than the HR group. Expression level of immune checkpoints, including CD28, CD27, IDO2, and others, were higher in the LR group. Multiple drugs approved by FAD, targeting ERS-related genes, were available for the treatment of LUAD. In summary, we established a stable prognostic model based on ERS-related genes to help the classification of LUAD patients and looked for new treatment strategies from aspects of immunity, tumor mutation, and tumor stem cell infiltration.
  4. Med Oncol. 2022 May 15. 39(5): 73
      Heme-regulated inhibitor (HRI) kinase is a serine-threonine kinase, controlling the initiation of protein synthesis via phosphorylating α subunit of eIF2 on serine 51 residue, mainly in response to heme deprivation in erythroid cells. However, recent studies showed that HRI is also activated by several diverse signals, causing dysregulations in intracellular homeostatic mechanisms in non-erythroid cells. For instance, it was reported that the decrease in protein synthesis upon the 26S proteasomal inhibition by MG132 or bortezomib is mediated by increased eIF2α phosphorylation in an HRI-dependent manner in mouse embryonic fibroblast cells. The increase in eIF2α phosphorylation level through the activation of HRI upon 26S proteasomal inhibition is believed to protect cells against the buildup of misfolded and ubiquitinated proteins, having the potential to trigger the apoptotic response. In contrast, prolonged and sustained HRI-mediated eIF2α phosphorylation can induce cell death, which may involve ATF4 and CHOP expression. Altogether, these studies suggest that HRI-mediated eIF2α phosphorylation may be cytoprotective or cytotoxic depending on the cells, type, and duration of pharmacological agents used. It is thus hypothesized that both HRI activators, inducing eIF2α phosphorylation or HRI inhibitors causing disturbances in eIF2α phosphorylation, may be effective as novel strategies in cancer treatment if the balance in eIF2α phosphorylation is shifted in favor of autophagic or apoptotic response in cancer cells. It is here aimed to review the role of HRI in various biological mechanisms as well as the therapeutic potentials of recently developed HRI activators and inhibitors, targeting eIF2α phosphorylation in cancer cells.
    Keywords:  Cancer; HRI; Heme; Stress; eIF2