bims-istrec Biomed News
on Integrated stress response in cancer
Issue of 2022‒05‒15
five papers selected by
Vincenzo Ciminale’s Lab
Istituto Oncologico Veneto

  1. FASEB J. 2022 May;36 Suppl 1
      The Integrated Stress Response (ISR) plays a critical role in the adaptation and survival of tumor cells to exogenous and endogenous stresses. The ISR features four protein kinases (PERK, GCN2, PKR, and HRI), each activated by different stresses, that phosphorylate the eukaryotic translation initiation factor eIF2, resulting in repression of global protein synthesis. Paradoxically, eIF2 phosphorylation also enhances translation of select gene transcripts, including the transcription factor ATF4, which is central for ISR-directed gene transcription. Therefore, the ISR directs translational and transcriptional control that is critical for cancer stress adaptation. Moreover, eIF2 phosphorylation and ATF4 have recently been suggested to play a role in prostate cancer (PCa) growth and survival; however, the specific function of ISR kinases, their mode of activation, and the mechanisms by which the ISR facilitate PCa progression are unknown. We discovered that GCN2 is activated in a range of PCa cell lines, contributing to enhanced eIF2 phosphorylation and ATF4 expression. Genetic or pharmacological inhibition of GCN2 reduces growth in androgen-sensitive and castration-resistant PCa cell lines in culture and cell line-derived and patient-derived xenograft mouse models in vivo. Induction of GCN2 is accompanied by limitations of select amino acids and accumulation of cognate tRNAs that are reported to be activators of GCN2. A transcriptome analysis of PCa cells treated with a specific GCN2 small molecular inhibitor indicates that GCN2 is critical for expression of SLCgenes involved in metabolite transport. We found that GCN2 inhibition decreases intracellular amino acid levels accounting for reduced growth in PCa cells. Using CRISPR-based phenotypic screens and genome-wide gene expression analyses of wild-type and GCN2-depleted PCa cells, we confirmed the importance of the transporter genes in PCa fitness. One transporter, SLC3A2 (4F2), is induced by GCN2 and is essential for PCa proliferation. SLC3A2 engages with many nutrient transporters, allowing for their localization to the plasma membrane. Importantly, expression of SLC3A2 reduced GCN2 activation and rescued decreased amino acid levels and growth inhibition due to loss of GCN2. Our results indicate that select amino acid limitations activate GCN2 in PCa, resulting in the upregulation of key amino acid transporters, including 4F2 (SLC3A2), which provide for nutrient import to facilitate protein synthesis and metabolism required for PCa progression. We conclude that GCN2 and the ISR are promising therapeutic targets for both androgen-sensitive and castration-resistant prostate cancer.
  2. Int J Biol Sci. 2022 ;18(7): 2898-2913
      Although triple-negative breast cancer (TNBC) is the most refractory subtype among all breast cancers, it has been shown to have higher immune infiltration than other subtypes. We identified the marine-derived small molecule MHO7, which acts as a potent immunogenic cell death (ICD) inducer through the endoplasmic reticulum (ER) stress-C/EBP-homologous protein (CHOP) pathway, to treat TNBC. MHO7 exerted cytostatic and cytotoxic effects on TNBC cells at an IC50 of 0.96-1.75 µM and suppressed tumor growth with an approximately 80% inhibition rate at a dose of 60 mg/kg. In 4T1 cell tumor-bearing mice, 30 mg/kg MHO7 inhibited pulmonary metastasis with an efficacy of 70.26%. Transcriptome analyses revealed that MHO7 changed the transcription of genes related to ribosome and protein processes in the ER. MHO7 also triggered reactive oxygen species (ROS) generation and attenuated glutathione (GSH) levels, which caused excessive oxidative stress and ER stress via the PERK/eIF2α/AFT4/CHOP pathway and led to cell apoptosis. ER stress and ROS production facilitated the release of ICD-related danger-associated molecular patterns (DAMPs) from TNBC cells, which activated the immune response in vivo, as indicated by the release of antitumor cytokines such as IL-6, IL-1β, IFN-γ, and TNF-α, increases in CD86+ and MHC-II dendritic cells and CD4+ and CD8+ T cells and a decrease in regulatory T cells (Tregs). These results reveal that MHO7 triggers an aggressive stress response to amplify tumor immunogenicity and induce a robust immune response. This synergistic effect inhibits primary breast cancer growth and spontaneous metastasis in TNBC, providing a new strategy for TNBC treatment.
    Keywords:  C/EBP-homologous protein; endoplasmic reticulum stress; immunogenic cell death; oxidative stress; sesterterpene; triple-negative breast cancer
  3. Environ Toxicol. 2022 May 07.
      Pachymic acid has various pharmacological effects, including anti-inflammatory, antioxidant, immunomodulatory, and antitumor. However, the role of pachymic acid in cervical cancer remains unclear. So, we investigated the effects of pachymic acid in cervical cancer and elucidated the underlying mechanisms. We treated HeLa cells and normal cervical epithelial cells (HUCECs) with pachymic acid (0, 10, 20, 40, 80, or 160 μM) for 72 h, and found the cell activity was decreased in cells treated with 160 μM pachymic acid for 48 h or 80 μM pachymic acid for 72 h, while HUCECs viability without effect. Next, we observed that endoplasmic reticulum (ER) related gene expression, mitochondrial membrane potential (MMP) changes, ATP depletion, reactive oxygen species (ROS) generation and apoptosis were increased. Moreover, we observed that cytochrome C (Cytc) expression was increased and apoptosis-inducing factor (AIF) was decreased in the cytoplasm of pachymic acid-treated HeLa cells. Tauroursodeoxycholic acid (TUDCA) of ER stress inhibitor reversed the effects of pachymic acid on HeLa cells. Phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) of the AMPK pathway key protein was upregulated in pachymic acid-induced HeLa cells. Finally, we subcutaneously implanted HeLa cells into female nude mice and treated them with pachymic acid (50 mg/kg) for 3 weeks (5 days/week), and observed in pachymic acid induced xenograft mice, tumor growth was suppressed, cell apoptosis, ER-related gene expression, and ROS levels in tumor tissues were increased. Therefore, these findings demonstrated that pachymic acid plays an anti-tumor activity in cervical cancer through inducing ER stress, mitochondrial dysfunction, and activating the AMPK pathway.
    Keywords:  AMPK pathway; ER stress; cervical cancer; mitochondrial dysfunction; pachymic acid
  4. Oncotarget. 2022 ;13 642-658
      Glioblastoma multiforme (GBM) is one of the deadliest cancers of the brain. Its ability to infiltrate healthy brain tissues renders it difficult to remove surgically. Furthermore, it exhibits high rates of radio- and chemoresistance, making the survival rates of patients with GBM poor. Therefore, novel effective therapies for GBM remain urgently in demand. Niclosamide is an anti-helminthic drug and recently it has been receiving attention due to its reported anticancer effects in cancer models, including GBM. Furthermore, camptothecin (CPT) is a naturally-occurring alkaloid and has been previously reported to be a potential chemotherapeutic agent by targeting the nuclear topoisomerase I. In the present study, the possible combined chemotherapeutic effects of niclosamide and CPT on the human glioblastoma cell line U87 MG was investigated by MTT assay and western blot analysis. Niclosamide exhibited synergistic activities with CPT to suppress the proliferation of U87 MG cells. Additionally, niclosamide suppressed cell proliferation and induced cell death mainly by triggering ER stress and autophagy, whilst CPT induced cell apoptosis mainly through p53-mediated mitochondrial dysfunction and activation of the MAPK (ERK/JNK) pathways. Overall, these findings suggest that co-administration of niclosamide and CPT may provide a novel therapeutic treatment strategy for GBM.
    Keywords:  camptothecin; cancer; chemotherapy; glioblastoma; niclosamide
  5. Life Sci. 2022 May 06. pii: S0024-3205(22)00320-4. [Epub ahead of print] 120620
      In tumor cells, the endoplasmic reticulum (ER) plays an essential role in maintaining cellular proteostasis by stimulating unfolded protein response (UPR) underlying stress conditions. ER-associated degradation (ERAD) is a critical pathway of the UPR to protect cells from ER stress-induced apoptosis and the elimination of unfolded or misfolded proteins by the ubiquitin-proteasome system (UPS). 3-Hydroxy-3-methylglutaryl reductase degradation (HRD1) as an E3 ubiquitin ligase plays an essential role in the ubiquitination and dislocation of misfolded protein in ERAD. In addition, HRD1 can target other normal folded proteins. In various types of cancer, the expression of HRD1 is dysregulated, and it targets different molecules to develop cancer hallmarks or suppress the progression of the disease. Recent investigations have defined the role of HRD1 in drug resistance in types of cancer. This review focuses on the molecular mechanisms of HRD1 and its roles in cancer pathogenesis and discusses the worthiness of targeting HRD1 as a novel therapeutic strategy in cancer.
    Keywords:  Cancer; HRD1; Therapy resistance; Ubiquitination