bims-istrec Biomed News
on Integrated stress response in cancer
Issue of 2022‒05‒01
five papers selected by
Vincenzo Ciminale’s Lab
Istituto Oncologico Veneto

  1. J Immunother Cancer. 2022 Apr;pii: e004151. [Epub ahead of print]10(4):
      BACKGROUND: Retrospective clinical trials reported a reduced local relapse rate, as well as improved overall survival after injection of local anesthetics during cancer surgery. Here, we investigated the anticancer effects of six local anesthetics used in clinical practice.RESULTS: In vitro, local anesthetics induced signs of cancer cell stress including inhibition of oxidative phosphorylation, and induction of autophagy as well as endoplasmic reticulum (ER) stress characterized by the splicing of X-box binding protein 1 (XBP1s) mRNA, cleavage of activating transcription factor 6 (ATF6), phosphorylation of eIF2α and subsequent upregulation of activating transcription factor 4 (ATF4). Both eIF2α phosphorylation and autophagy required the ER stress-relevant eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, best known as PERK). Local anesthetics also activated two hallmarks of immunogenic cell death, namely, the release of ATP and high-mobility group box 1 protein (HMGB1), yet failed to cause the translocation of calreticulin (CALR) from the ER to the plasma membrane. In vivo, locally injected anesthetics decreased tumor growth and improved survival in several models of tumors established in immunocompetent mice. Systemic immunotherapy with PD-1 blockade or intratumoral injection of recombinant CALR protein, increased the antitumor effects of local anesthetics. Local anesthetics failed to induce antitumor effects in immunodeficient mice or against cancers unable to activate ER stress or autophagy due to the knockout of EIF2AK3/PERK or ATG5, respectively. Uncoupling agents that inhibit oxidative phosphorylation and induce autophagy and ER stress mimicked the immune-dependent antitumor effects of local anesthetics.
    CONCLUSION: Altogether, these results indicate that local anesthetics induce a therapeutically relevant pattern of immunogenic stress responses in cancer cells.
    Keywords:  Adjuvants, Immunologic; Cytotoxicity, Immunologic; Drug Evaluation, Preclinical; Drug Therapy, Combination; Immunotherapy
  2. Data Brief. 2022 Jun;42 108126
      Isoginkgetin (IGG) is a compound originally derived from the leaves of Ginkgo biloba trees. It was subsequently identified through a chemical screen to be an inhibitor of both the major and minor spliceosome, with an IC50 value of 30 µM [1]. Little is currently known about the overall effects of spliceosome inhibition on human cells. Here, we treated HCT116 and a p53 null subline of colon cancer cells with 30 µM IGG for 8 hours. Total RNA was isolated, and Affymetrix oligonucleotide microarray analysis was completed using samples from two biologically independent experiments. A relatively small number of transcripts were differentially expressed in these cell lines. There was considerable overlap in the upregulated but not the downregulated transcripts. PANTHER Reactome analysis of these shared upregulated transcripts identified enriched pathways involving the ATF4 transcription factor important in the integrated stress response [2].
    Keywords:  ATF4; Isoginkgetin; Microarray; Spliceosome inhibition
  3. Int J Gen Med. 2022 ;15 4303-4319
      Purpose: Endoplasmic reticulum (ER) stress has a significant effect on cancer cells. Increasing numbers of studies indicate that long non-coding RNAs (lncRNAs) promote the development of colon adenocarcinoma (COAD), but the relationship between ER stress-related lncRNAs and the prognosis of COAD remains unclear. The aim of the current study was to construct and validate an ER stress-related lncRNA prognostic signature to predict COAD prognoses.Methods: Gene expression data and clinical information from the Cancer Genome Atlas and the Gene Expression Omnibus with COAD were downloaded and analyzed. Cox regression and least absolute shrinkage and selection operator regression were then used to develop an ER stress-related lncRNA signature. COAD patients were then divided into high-risk and low-risk groups based on the median risk score to analyze prognoses. Tumor mutation burdens (TMBs) and the differences in copy number variations (CNVs) between the two groups were also analyzed. Lastly, gene set enrichment analysis (GSEA) was used to explore the enrichment pathways and biological processes associated with differentially expressed genes in the high-risk and low-risk groups, and lncRNA expression in the model was validated via quantitative real-time PCR in colon cancer and paracancerous tissues.
    Results: A signature including 8 ER stress-related lncRNAs was constructed. COAD prognoses were significantly poorer in the high-risk group than in the low-risk group. There were few differences in TMBs and CNVs between the two groups. In GSEA analysis, in the high-risk group highly expressed genes associated with extracellular matrix pathways were significantly enriched.
    Conclusion: The 8-ER stress-related lncRNA derived from the present study is a potential indicator of COAD prognosis.
    Keywords:  GEO; TCGA; colon adenocarcinoma; endoplasmic reticulum stress; long non-coding RNA
  4. Cell Death Dis. 2022 Apr 23. 13(4): 400
      Renal cell carcinoma (RCC) is one of the most lethal genitourinary malignancies with poor prognoses, since it is largely resistant to chemotherapy, radiotherapy, and targeted therapy. The persistence of cancer stem cells (CSCs) is the major cause of treatment failure with RCC. Recent evidence showed that dopamine receptor D2 (DRD2)-targeting antipsychotic drugs such as penfluridol exert oncostatic effects on several cancer types, but the effect of penfluridol on RCC remains unknown. Here, we uncovered penfluridol suppressed in vitro cell growth and in vivo tumorigenicity of various RCC cell lines (Caki-1, 786-O, A498, and ACHN) and enhanced the Sutent (sunitinib)-triggered growth inhibition on clear cell (cc)RCC cell lines. Mechanistically, upregulation of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) was critical for autophagy-mediated apoptosis induced by penfluridol. Transcriptional inhibition of OCT4 and Nanog via inhibiting GLI1 was important for penfluridol-induced stemness and proliferation inhibition. The anticancer activities of penfluridol on ccRCC partially occurred through DRD2. In clinical ccRCC specimens, positive correlations of DRD2 with GLI1, OCT4, and Nanog were observed and their expressions were correlated with worse prognoses. Summarizing, DRD2 antagonists such as penfluridol induce UPR signaling and suppress the GLI1/OCT4/Nanog axis in ccRCC cells to reduce their growth through inducing autophagy-mediated apoptosis and stemness inhibition. These drugs can be repurposed as potential agents to treat ccRCC patients.
  5. Cell Death Dis. 2022 Apr 28. 13(4): 410
      Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy and have a dismal 4-year event-free survival (EFS) of 37%. We have previously shown that mTOR activation contributes to AT/RT's aggressive growth and poor survival. Targeting the mTOR pathway with the dual mTORC1/2 inhibitor TAK-228 slows tumor growth and extends survival in mice bearing orthotopic xenografts. However, responses are primarily cytostatic with limited durability. The aim of this study is to understand the impact of mTOR inhibitors on AT/RT signaling pathways and design a rational combination therapy to drive a more durable response to this promising therapy. We performed RNASeq, gene expression studies, and protein analyses to identify pathways disrupted by TAK-228. We find that TAK-228 decreases the expression of the transcription factor NRF2 and compromises AT/RT cellular defenses against oxidative stress and apoptosis. The BH3 mimetic, Obatoclax, is a potent inducer of oxidative stress and apoptosis in AT/RT. These complementary mechanisms of action drive extensive synergies between TAK-228 and Obatoclax slowing AT/RT cell growth and inducing apoptosis and cell death. Combination therapy activates the integrative stress response as determined by increased expression of phosphorylated EIF2α, ATF4, and CHOP, and disrupts the protective NOXA.MCL-1.BIM axis, forcing stressed cells to undergo apoptosis. Combination therapy is well tolerated in mice bearing orthotopic xenografts of AT/RT, slows tumor growth, and extends median overall survival. This novel combination therapy could be added to standard upfront therapies or used as a salvage therapy for relapsed disease to improve outcomes in AT/RT.