The integrated stress response (ISR) is critical for cancer cell survival during stress stimuli and has been implicated in the resistance to cancer therapeutics, in which the mechanism, however, is ...poorly understood. Here, we showed that paclitaxel, the major chemotherapy drug for breast cancer, induced ISR and phosphorylated ser51 residue of EIF2S1 by EIF2AK3 and EIF2AK4. When exposed to paclitaxel, cancer cells activated the EIF2AK3/EIF2AK4‐pEIF2S1‐ATF4 axis and maintained redox homoeostasis by inducing expression of the major antioxidant enzymes HMOX1, SHMT2 and SLC7A11. Paclitaxel‐mediated cell death was significantly increased following loss of ISR or ATF4 expression. This sensitizing effect could be partially rescued by Trolox, a ROS scavenger. We demonstrated that the alternative initiation factor EIF2A was essential for cancer cell survival after paclitaxel‐mediated ISR both in vitro and in vivo. Moreover, patients with breast cancer exhibited higher ISR after chemotherapy, and the elevated mRNA levels of HMOX1, SHMT2 and EIF2A were correlated with poor prognosis. Collectively, our findings reveal a novel mechanism for paclitaxel resistance and suggest that targeting EIF2A combined with ISR agonist may be a potential treatment regimen to overcome drug resistance for breast cancer.
Radiation-induced lung fibrosis (RILF) is a severe side effect of radiotherapy in lung cancer patients that presents as a progressive pulmonary injury combined with chronic inflammation and ...exaggerated organ repair. RILF is a major barrier to improving the cure rate and well-being of lung cancer patients because it limits the radiation dose that is required to effectively kill tumor cells and diminishes normal lung function. Although the exact mechanism is unclear, accumulating evidence suggests that various cells, cytokines and regulatory molecules are involved in the tissue reorganization and immune response modulation that occur in RILF. In this review, we will summarize the general symptoms, diagnostics, and current understanding of the cells and molecular factors that are linked to the signaling networks implicated in RILF. Potential approaches for the treatment of RILF will also be discussed. Elucidating the key molecular mediators that initiate and control the extent of RILF in response to therapeutic radiation may reveal additional targets for RILF treatment to significantly improve the efficacy of radiotherapy for lung cancer patients.
Pancreatic cancer is a highly malignant tumour of the digestive tract which is difficult to diagnose and treat. Approximately 90% of cases arise from ductal adenocarcinoma of the glandular ...epithelium. The morbidity and mortality of the disease have increased significantly in recent years. Its 5‐year survival rate is <1% and has one of the worst prognoses amongst malignant tumours. Pancreatic cancer has a low rate of early‐stage diagnosis, high surgical mortality and low cure rate. Selenium compounds produced by selenoamino acid metabolism may promote a large amount of oxidative stress and subsequent unfolded reactions and endoplasmic reticulum stress by consuming the NADPH in cells, and eventually lead to apoptosis, necrosis or necrotic cell death. In this study, we first identified DIAPH3 as a highly expressed protein in the tissues of patients with pancreatic cancer, and confirmed that DIAPH3 promoted the proliferation, anchorage‐independent growth and invasion of pancreatic cancer cells using overexpression and interference experiments. Secondly, bioinformatics data mining showed that the potential proteins interacted with DIAPH3 were involved in selenoamino acid metabolism regulation. Selenium may be incorporated into selenoprotein synthesis such as TrxR1 and GPX4, which direct reduction of hydroperoxides or resist ferroptosis, respectively. Our following validation confirmed that DIAPH3 promoted selenium content and interacted with the selenoprotein RPL6, a ribosome protein subunit involved in selenoamino acid metabolism. In addition, we verified that DIAPH3 could down‐regulate cellular ROS level via up‐regulating TrxR1 expression. Finally, nude mice xenograft model experimental results demonstrate DIAPH3 knock down could decrease tumour growth and TrxR1 expression and ROS levels in vivo. Collectively, our observations indicate DIAPH3 could promote pancreatic cancer progression by activating selenoprotein TrxR1‐mediated antioxidant effects.
Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation ...(FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A
, CPT2
, ACAD9
cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. The FAO-CD47 axis may be targeted to improve GBM control by eliminating the radioresistant phagocytosis-proofing tumor cells in GBM radioimmunotherapy.
Radiation resistance is a critical problem in radiotherapy for cancer. Radiation kills tumor cells mainly through causing DNA damage. Thus, efficiency of DNA damage repair is one of the most ...important factors that limits radiotherapy efficacy. Glutamine physiologically functions to generate protein and nucleotides. Here, we study the impact of glutamine metabolism on cancer therapeutic responses, in particular under irradiation-induced stress. We show that radiation-resistant cells possessed low glycolysis, mitochondrial respiration, and TCA cycle but high glutamine anabolism. Transcriptome analyses revealed that glutamine synthetase (GS), an enzyme catalyzing glutamate and ammonia to glutamine, was responsible for the metabolic alteration. ChIP and luciferase reporter assays revealed that GS could be transcriptionally regulated by STAT5. Knockdown of GS delayed DNA repair, weakened nucleotide metabolism, and enhanced radiosensitivity both in vitro and in vivo. Our data show that GS links glutamine metabolism to radiotherapy response through fueling nucleotide synthesis and accelerating DNA repair.
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•Radioresistant cancer cells reprogram metabolic flux toward glutamine anabolism•GS promotes cellular nucleotide synthesis for efficient DNA repair•High expression of GS facilitates growth of cancer cells under radiation stress•GS is transcriptionally regulated by STAT5
Radiation resistance is one of the limiting factors for therapeutic efficacy and results in cancer recurrence. Fu et al. identify GS as a switch that drives cellular metabolic flux toward nucleotide synthesis for efficient DNA repair and thus leads to radiation resistance of cancer cells.
Although the efficacy of cancer radiotherapy (RT) can be enhanced by targeted immunotherapy, the immunosuppressive factors induced by radiation on tumor cells remain to be identified. Here, we report ...that CD47-mediated anti-phagocytosis is concurrently upregulated with HER2 in radioresistant breast cancer (BC) cells and RT-treated mouse syngeneic BC. Co-expression of both receptors is more frequently detected in recurrent BC patients with poor prognosis. CD47 is upregulated preferentially in HER2-expressing cells, and blocking CD47 or HER2 reduces both receptors with diminished clonogenicity and augmented phagocytosis. CRISPR-mediated CD47 and HER2 dual knockouts not only inhibit clonogenicity but also enhance macrophage-mediated attack. Dual antibody of both receptors synergizes with RT in control of syngeneic mouse breast tumor. These results provide the evidence that aggressive behavior of radioresistant BC is caused by CD47-mediated anti-phagocytosis conjugated with HER2-prompted proliferation. Dual blockade of CD47 and HER2 is suggested to eliminate resistant cancer cells in BC radiotherapy.
Highlights • Post translational modifications of P53 play critical roles in cellular response to radiation. • P53 acetylation/deacetylation modulates key cellular events involved in radioresistance. ...• Targeting enzymes participating in p53 acetylation/deacetylation provides a promising strategy for radiosensitization.
Epithelial‐to‐mesenchymal transition (EMT) is a dynamic transitional state from the epithelial to mesenchymal phenotypes. Numerous studies have suggested that EMT and its intermediate states play ...important roles in tumor invasion and metastasis. To identify novel regulatory molecules of EMT, we screened a siRNA library targeting human 720 kinases in A549 lung adenocarcinoma cells harboring E‐cadherin promoter‐luciferase reporter vectors. NIMA‐related kinase‐4 (NEK4) was identified and characterized as a positive regulator of EMT in the screening. Suppression of NEK4 resulted in the inhibition of cell migration and invasion, accompanying with an increased expression of cell adhesion‐related proteins such as E‐cadherin and ZO1. Furthermore, NEK4 knockdown caused the decreased expression of the transcriptional factor Zeb1 and Smads proteins, which are known to play key roles in EMT regulation. Consistently, overexpression of NEK4 resulted in the decreased expression of E‐cadherin and increased expression of Smad3. Using a mouse model with tail vein injection of NEK4 knockdown stable cell line, we found a lower rate of tumor formation and metastasis of the NEK4‐knockdown cells in vivo. Thus, this study demonstrates NEK4 as a novel kinase involved in regulation of EMT and suggests that NEK4 may be further explored as a potential therapeutic target for lung cancer metastasis.
Intrahepatic cholangiocarcinoma (ICC) ranks as the second most malignant type of primary liver cancer with a high degree of incidence and a very poor prognosis. Fat mass and obesity-associated ...protein (FTO) functions as an eraser of the RNA m
A modification, but its roles in ICC tumorigenesis and development remain unknown. We showed here that the protein level of FTO was downregulated in clinical ICC samples and cell lines and that FTO expression was inversely correlated with the expression of CA19-9 and micro-vessel density (MVD). A Kaplan-Meier survival analysis showed that a low expression of
predicted poor prognosis in ICC.
, decreased endogenous expression of
obviously reduced apoptosis of ICC cells. Moreover,
suppressed the anchorage-independent growth and mobility of ICC cells. Through mining the database, FTO was found to regulate the integrin signaling pathway, inflammation signaling pathway, epidermal growth factor receptor (EGFR) signaling pathway, angiogenesis, and the pyrimidine metabolism pathway. RNA decay assay showed that oncogene
mRNA stability was impaired by FTO. In addition, the overexpression of FTO suppressed tumor growth
. In conclusion, our study demonstrated the critical roles of FTO in ICC.
Radiation therapy elicits profound alterations in gene expression in tumor cells. This study aims to determine the dynamic changes in the expression of immunity-associated genes in nasopharyngeal ...carcinoma (NPC) cells upon radiation therapy.
The study was performed using NPC patient-derived tumor xenograft tumors, cell lines, CCR4+ CD8 T cells sorted from peripheral blood mononuclear cells of healthy volunteers, and TCGA-derived bulk RNA-seq or single-cell RNA-seq (scRNA-seq) data sets. Patient-derived tumor xenograft tumors or cell lines were irradiated and collected for bulk RNA sequencing or for CCL22 expression and release detection. Malignant phenotypes and radiosensitivity were assessed in cells with or without overexpression of CCL22 or recombinant CCL22 treatment in the presence or absence of irradiation. TCGA data sets were used for uncovering CCR4 status in subtypes of T cells. CCL22 in supernatants, cell lysates, or serum samples was measured with enzyme-linked immunosorbent assay.
CCL22 was significantly increased in the irradiated patient-derived tumor xenograft tumors, the supernatants and cell lysates collected from irradiated NPC cell lines, and the serum of patients who received radiation therapy. No alterations of malignant phenotypes were found in tumor cells with CCL22 overexpression or recombinant CCL22 treatment. Kaplan-Meier analysis revealed that CCL22 or its receptor CCR4 positively correlated with cytotoxic T lymphocyte signatures, and high expression of CCL22 or CCR4 was associated with better prognosis for patients with NPC. scRNA-seq data set–based analysis demonstrated that CCR4 was expressed in multiple subtypes of T cells, including effector CD8 T cells. Chemotaxis assay indicated that CCR4+ CD8 T cells could be recruited by CCL22 treatment.
The radiation-enhanced release of CCL22 from NPC cells promotes migration of CCR4 + effector CD8 T cells, which might partially be associated with radiation therapy–mediated antitumor immunity.
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