bims-istrec Biomed News
on Integrated stress response in cancer
Issue of 2022‒02‒13
seven papers selected by
Vincenzo Ciminale’s Lab
Istituto Oncologico Veneto

  1. FASEB J. 2022 Mar;36(3): e22201
      Oncogene activation, massive proliferation, and increased nutrient demands often result in nutrient and oxygen deprivation in solid tumors including breast cancer (BC), leading to the induction of oxidative stress and endoplasmic reticulum (ER) stress, and subsequently triggering integrated stress response (ISR). To elucidate the role of long non-coding RNAs (lncRNAs) in the ISR of BC, we performed transcriptome analyses and identified a lncRNA, UBA6-AS1, which was upregulated upon amino acid deprivation and ER stress. UBA6-AS1 was preferentially induced in triple-negative BC (TNBC) cells deprived of arginine or glutamine, two critical amino acids required for cancer cell growth, or treated with ER stress inducers. Mechanistically, UBA6-AS1 was regulated through the GCN2/eIF2α/ATF4 pathway, one of the major routes mediating ISR in amino acid sensing. In addition, both in vitro and in vivo assays indicated that UBA6-AS1 promoted TNBC cell survival when cells encountered metabolic stress, implicating a regulatory role of UBA6-AS1 in response to intratumoral metabolic stress during tumor progression. Moreover, PARP1 expression and activity were positively regulated by the GCN2/UBA6-AS1 axis upon amino acid deprivation. In conclusion, our data suggest that UBA6-AS1 is a novel lncRNA regulating ISR upon metabolic stress induction to promote TNBC cell survival. Furthermore, the GCN2-ATF4 axis is important for UBA6-AS1 induction to enhance PARP1 activity and could serve as a marker for the susceptibility of PARP inhibitors in TNBC.
    Keywords:   UBA6-AS1 ; UBA6-DT ; PARP1; amino acid restriction; integrated stress response; long non-coding RNA
  2. Am J Cancer Res. 2022 ;12(1): 327-336
      Six Transmembrane Protein of Prostate 2 (STAMP2) is critical for prostate cancer (PCa) growth. We previously showed that STAMP2 regulates the expression of stress induced transcription factor ATF4, which is implicated in starvation-induced autophagy. We therefore investigated whether STAMP2 is involved in the regulation of autophagy in PCa cells. Here we show that STAMP2 suppresses autophagy in PCa cells through modulation of the integrated stress response axis. We also find that STAMP2 regulates mitochondrial respiration. These findings suggest that STAMP2 has significant metabolic effects through mitochondrial function and autophagy, both of which support PCa growth.
    Keywords:  ATF4; Prostate cancer; STAMP2; autophagy; eIF2α; integrated stress response; mitochondria
  3. Cancer Res. 2022 Feb 11. pii: canres.2218.2021. [Epub ahead of print]
      G9a and EZH2 are two histone methyltransferases commonly upregulated in several cancer types, yet the precise roles that these enzymes play cooperatively in cancer is unclear. We demonstrate here that frequent concurrent upregulation of both G9a and EZH2 occurs in several human tumors. These methyltransferases cooperatively repressed molecular pathways responsible for tumor cell death. In genetically distinct tumor subtypes, concomitant inhibition of G9a and EZH2 potently induced tumor cell death, highlighting the existence of tumor cell survival dependency at the epigenetic level. G9a and EZH2 synergistically repressed expression of genes involved in the induction of endoplasmic reticulum (ER) stress and the production of reactive oxygen species. IL24 was essential for the induction of tumor cell death and was identified as a common target of G9a and EZH2. Loss-of-function of G9a and EZH2 activated the IL24-ER stress axis and increased apoptosis in cancer cells while not affecting normal cells. These results indicate that G9a and EZH2 promotes the evasion of ER stress-mediated apoptosis by repressing IL24 transcription, therefore suggesting that their inhibition may represent a potential therapeutic strategy for solid cancers.
  4. Front Physiol. 2021 ;12 782525
      Cell proliferation in pancreatic cancer is determined by a complex network of signaling pathways. Despite the extensive understanding of these protein-mediated signaling processes, there are no significant drug discoveries that could considerably improve a patient's survival. However, the recent understanding of lipid-mediated signaling gives a new perspective on the control of the physiological state of pancreatic cells. Lipid signaling plays a major role in the induction of cytocidal autophagy and can be exploited using synthetic lipids to induce cell death in pancreatic cancer cells. In this work, we studied the activity of a synthetic lipid, tri-2-hydroxyarachidonein (TGM4), which is a triacylglycerol mimetic that contains three acyl moieties with four double bonds each, on cellular and in vivo models of pancreatic cancer. We demonstrated that TGM4 inhibited proliferation of Mia-PaCa-2 (human pancreatic carcinoma) and PANC-1 (human pancreatic carcinoma of ductal cells) in in vitro models and in an in vivo xenograft model of Mia-PaCa-2 cells. In vitro studies demonstrated that TGM4 induced cell growth inhibition paralleled with an increased expression of PARP and CHOP proteins together with the presence of sub-G0 cell cycle events, indicating cell death. This cytocidal effect was associated with elevated ER stress or autophagy markers such as BIP, LC3B, and DHFR. In addition, TGM4 activated peroxisome proliferator-activated receptor gamma (PPAR-γ), which induced elevated levels of p-AKT and downregulation of p-c-Jun. We conclude that TGM4 induced pancreatic cell death by activation of cytocidal autophagy. This work highlights the importance of lipid signaling in cancer and the use of synthetic lipid structures as novel and potential approaches to treat pancreatic cancer and other neoplasias.
    Keywords:  autophagy; cancer; cell death; oncology; pancreas; signal transduction; synthetic lipid
  5. Redox Rep. 2022 Dec;27(1): 32-44
      Objectives: Lycium barbarum polysaccharide (LBP) is a natural polysaccharide extracted from Lycium barbarum that has anti-inflammatory, anti-apoptotic and anti-aging effects, and plays a role in the prevention and treatment of various diseases. In this study, we investigated the therapeutic effect of LBP on particulate matter 2.5 (PM2.5)-induced skin damage.Methods: Cell viability was analyzed by MTT and LDH assays. Apoptosis was analyzed by Annexin V-FITC/PI staining. Oxidative stress/damage were assessed by intracellular ROS levels, MDA content and SOD activity. The intracellular protein expression was analyzed by Western blot. Mitochondrial damage was assayed by mitochondrial membrane potential with JC-1 probe. LC3-GFP adenovirus was transfected into HaCaT cells to analyze intracellular autophagosome levels.Results: In PM2.5-treated HaCaT cells, LBP pretreatment reduced PM2.5-induced cytotoxicity, ameliorated cell morphology and reduced cell apoptosis. LBP also inhibited the expression levels of GRP78 and CHOP, reduced the conversion of LC3I to LC3II, inhibited Bax protein and activated Bcl-2 protein. Furthermore, LBP inhibited PM2.5-induced mitochondrial autophagy (mitophagy) and mitochondrial damage. PM2.5-induced autophagy was regulated by endoplasmic reticulum (ER) stress.Conclusion: LBP protects skin cells from PM2.5-induced cytotoxicity by regulating the oxidative stress-ER stress-autophagy-apoptosis signaling axis, revealing that LBP has a great potential for the skin protection.
    Keywords:  Lycium barbarum polysaccharide (LBP); PM2.5; antioxidant; apoptosis; autophagy; endoplasmic reticulum (ER) stress; mitochondrial damage; oxidative damage
  6. Acta Pharm Sin B. 2022 Jan;12(1): 210-227
      Pancreatic adenocarcinoma (PAAD) is one of the most lethal malignancies. Although gemcitabine (GEM) is a standard treatment for PAAD, resistance limits its application and therapy. Secoemestrin C (Sec C) is a natural compound from the endophytic fungus Emericella, and its anticancer activity has not been investigated since it was isolated. Our research is the first to indicate that Sec C is a broad-spectrum anticancer agent and could exhibit potently similar anticancer activity both in GEM-resistant and GEM-sensitive PAAD cells. Interestingly, Sec C exerted a rapid growth-inhibiting effect (80% death at 6 h), which might be beneficial for patients who need rapid tumor shrinkage before surgery. Liquid chromatography/mass spectrometry and N-acetyl-l-cysteine (NAC) reverse assays show that Sec C sulfates cysteines to disrupt disulfide-bonds formation in endoplasmic reticulum (ER) proteins to cause protein misfolding, leading to ER stress and disorder of lipid biosynthesis. Microarray data and subsequent assays show that ER stress-mediated ER-associated degradation (ERAD) ubiquitinates and downregulates YAP to enhance ER stress via destruction complex (YAP-Axin-GSK-βTrCP), which also elucidates a unique degrading style for YAP. Potent anticancer activity in GEM-resistant cells and low toxicity make Sec C a promising anti-PAAD candidate.
    Keywords:  ER stress inducer; Fast shrinkage; Lipid droplet formation; Pancreatic cancer; Resistance; Secoemestrin C; YAP degradation; YAP destruction complex
  7. Exp Hematol Oncol. 2022 Feb 09. 11(1): 5
      BACKGROUND: Multiple myeloma (MM) remains an incurable malignancy, despite the advent of therapies such as proteosome inhibitors (PIs) that disrupt protein homeostasis and induce ER stress. We have pursued inhibition of geranylgeranyl diphosphate synthase (GGDPS) as a novel mechanism by which to target protein homeostasis in MM cells. GGDPS inhibitors (GGSI) disrupt Rab geranylgeranylation, which in turn results in perturbation of Rab-mediated protein trafficking, leading to accumulation of intracellular monoclonal protein, induction of ER stress and apoptosis. Our lead GGSI, RAM2061, has demonstrated favorable pharmacokinetic properties and in vivo efficacy. Here we sought to evaluate if combination therapy with GGSI and PI would result in enhanced disruption of the unfolded protein response (UPR) and increase anti-MM efficacy.METHODS: MTT assays were conducted to evaluate the cytotoxic effects of combining RAM2061 with bortezomib in human MM cells. The effects of RAM2061 and/or PI (bortezomib or carfilzomib) on markers of UPR and apoptosis were evaluated by a combination of immunoblot (ATF4, IRE1, p-eIF2a, cleaved caspases and PARP), RT-PCR (ATF4, ATF6, CHOP, PERK, IRE1) and flow cytometry (Annexin-V). Induction of immunogenic cell death (ICD) was assessed by immunoblot (HMGB1 release) and flow cytometry (calreticulin translocation). Cell assays were performed using both concurrent and sequential incubation with PIs. To evaluate the in vivo activity of GGSI/PI, a flank xenograft using MM.1S cells was performed.
    RESULTS: Isobologram analysis of cytotoxicity data revealed that sequential treatment of bortezomib with RAM2061 has a synergistic effect in MM cells, while concurrent treatment was primarily additive or mildly antagonistic. The effect of PIs on augmenting RAM2061-induced upregulation of UPR and apoptotic markers was dependent on timing of the PI exposure. Combination treatment with RAM2061 and bortezomib enhanced activation of ICD pathway markers. Lastly, combination treatment slowed MM tumor growth and lengthened survival in a MM xenograft model without evidence of off-target toxicity.
    CONCLUSION: We demonstrate that GGSI/PI treatment can potentiate activation of the UPR and apoptotic pathway, as well as induce upregulation of markers associated with the ICD pathway. Collectively, these findings lay the groundwork for future clinical studies evaluating combination GGSI and PI therapy in patients with MM.