Abstract:
BACKGROUND:The histone methyltransferase G9a has recently been identified as a potential target for epigenetic therapy of acute myeloid leukemia (AML). However, the effect of G9a inhibition on leukemia stem cells (LSCs), which are responsible for AML drug resistance and recurrence, is unclear. In this study, we investigated the underlying mechanisms of the LSC resistance to G9a inhibition. METHODS:We evaluated the effects of G9a inhibition on the unfolded protein response and autophagy in AML and LSC-like cell lines and in primary CD34+CD38- leukemic blasts from patients with AML and investigated the underlying mechanisms. The effects of treatment on cells were evaluated by flow cytometry, western blotting, confocal microscopy, reactive oxygen species (ROS) production assay. RESULTS:The G9a inhibitor BIX-01294 effectively induced apoptosis in AML cell lines; however, the effect was limited in KG1 LSC-like cells. BIX-01294 treatment or siRNA-mediated G9a knockdown led to the activation of the PERK/NRF2 pathway and HO-1 upregulation in KG1 cells. Phosphorylation of p38 and intracellular generation of reactive oxygen species (ROS) were suppressed. Pharmacological or siRNA-mediated inhibition of the PERK/NRF2 pathway synergistically enhanced BIX-01294-induced apoptosis, with suppressed HO-1 expression, increased p38 phosphorylation, and elevated ROS generation, indicating that activated PERK/NRF2 signaling suppressed ROS-induced apoptosis in KG1 cells. By contrast, cotreatment of normal hematopoietic stem cells with BIX-01294 and a PERK inhibitor had no significant proapoptotic effect. Additionally, G9a inhibition induced autophagy flux in KG1 cells, while autophagy inhibitors significantly increased the BIX-01294-induced apoptosis. This prosurvival autophagy was not abrogated by PERK/NRF2 inhibition. CONCLUSIONS:PERK/NRF2 signaling plays a key role in protecting LSCs against ROS-induced apoptosis, thus conferring resistance to G9a inhibitors. Treatment with PERK/NRF2 or autophagy inhibitors could overcome resistance to G9a inhibition and eliminate LSCs, suggesting the potential clinical utility of these unique targeted therapies against AML.
journal_name
J Exp Clin Cancer Resjournal_title
Journal of experimental & clinical cancer research : CRauthors
Jang JE,Eom JI,Jeung HK,Chung H,Kim YR,Kim JS,Cheong JW,Min YHdoi
10.1186/s13046-020-01565-3subject
Has Abstractpub_date
2020-04-15 00:00:00pages
66issue
1eissn
0392-9078issn
1756-9966pii
10.1186/s13046-020-01565-3journal_volume
39pub_type
杂志文章abstract:BACKGROUND:One-third of estrogen (ER+) and/or progesterone receptor-positive (PGR+) breast tumors treated with Tamoxifen (TAM) do not respond to initial treatment, and the remaining 70% are at risk to relapse in the future. Estrogen-related receptor gamma (ESRRG, ERRγ) is an orphan nuclear receptor with broad, structur...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-015-0150-9
更新日期:2015-05-15 00:00:00
abstract::This study was carried out statistically to evaluate the present situation of carcinoids and related endocrine variants in the uterine cervix. A total of 205 patients who had been reported on in world-wide literature were divided into two groups; one, as a carcinoid group, consisting of 81 patients with carcinoids, 49...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2001-09-01 00:00:00
abstract:BACKGROUND:Mucins are key components of the mucosal barrier in the stomach that protects epithelia from carcinogenic effects of chronic inflammation. Analysis of The Cancer Genome Atlas database indicated that mucin-17 (MUC17) was more highly expressed in gastric cancer (GC) specimens, with favourable prognosis for pat...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-019-1279-8
更新日期:2019-07-01 00:00:00
abstract:BACKGROUND:Metastasis is the primary cause of death in renal cell carcinoma (RCC). Loss of cell-to-cell adhesion, including tight junctions (TJs) is the initial step in the process of metastasis. Claudin-7 (CLDN7) is a major component of TJs. However, the clinical significance and its regulation of kidney tumorigenesis...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-018-0924-y
更新日期:2018-11-14 00:00:00
abstract:BACKGROUND:Metastasis in breast cancer is a vital concern in treatment because most women with primary breast cancer have micrometastases to distant sites at diagnosis. As a member of the inhibitor of apoptosis protein (IAP) family, survivin has been proposed as an attractive target for new anticancer interventions. In...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-27-46
更新日期:2008-09-25 00:00:00
abstract:BACKGROUND:The bromodomain and extra-terminal domain (BET) inhibitor is a type of anti-tumor agent, currently being evaluated in phase I and II clinical trials for cancer therapy. It can decrease MYC expression levels and cause effective anti-tumor effects in diverse human cancers. However, its cytotoxic effect and rel...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-019-1082-6
更新日期:2019-02-15 00:00:00
abstract::After aggressive surgery and chemotherapy, patients (PTS) with advanced solid tumors have often an impaired immune function that may facilitate tumor relapse. We have demonstrated, in a phase IB study, that administering low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA), there was a significant improvement o...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 临床试验,杂志文章
doi:
更新日期:2003-12-01 00:00:00
abstract:BACKGROUND:Tumor-associated macrophages (TAMs) and tumor cells are important components of the tumor microenvironment. M2 polarization of TAMs, which is a major actor in breast cancer malignancy and metastasis, can be induced by breast cancer cells. However, the potential mechanisms of the interaction between breast ca...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-020-01676-x
更新日期:2020-09-17 00:00:00
abstract::The aim of the present study was to assess the role of virtual cystoscopy in the identification of bladder tumors. Fifteen patients (11 men and 4 women, median age: 61 years, range: 46-74 years) with a positive finding of bladder tumor at fiber-optic cystoscopy were studied by multislice-CT. Scans were downloaded to a...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2003-03-01 00:00:00
abstract:BACKGROUND:This is a retrospective cross sectional study aimed to verify whether Multiplex Ligation-dependent Probe Amplification (MLPA), a quantitative molecular assay, may represent a valuable reflex test in breast cancer with equivocal HER2 expression by immunohistochemistry and HER2 gene signals/nucleus (s/n) rangi...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-017-0613-2
更新日期:2017-10-13 00:00:00
abstract:BACKGROUND:Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. ERα has been identified to promote the growth of primary breast cancer, however, it can also antagonize sign...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-019-1112-4
更新日期:2019-03-01 00:00:00
abstract::This study was carried out to provide extensive information obtained from statistical analysis of laryngeal endocrinomas for the use of investigators working in this particular research field. A total of 278 patients with both typical and atypical varieties of carcinoids, and with small/oat cell carcinomas (SCC/OCC) e...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2002-03-01 00:00:00
abstract::The aim of this study was to assess the efficiency of the radioguided localization and excision technique using radiopharmaceuticals injected directly or close to occult breast lesions. We studied thirty-two consecutive patients with thirty-six occult breast lesions detected mammographically or ultrasonically categori...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 临床试验,杂志文章
doi:
更新日期:2007-09-01 00:00:00
abstract:BACKGROUND:Classical Kaposi's Sarcoma (cKS) is a rare vascular tumor, which develops in subjects infected with Human Herpesvirus-8 (HHV-8). Beside the host predisposing factors, viral genetic variants might possibly be related to disease development. The aim of this study was to identify HHV-8 variants in patients with...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-014-0119-0
更新日期:2015-01-16 00:00:00
abstract::In papillary thyroid carcinoma lymphnode metastases at presentation do not seem to adversely affect survival, but do increase the risk of loco-regional tumor recurrence. The value of systematic versus selective lymphadenectomy is far less standardized, whereas the role of postoperative radioiodine in preventing either...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 临床试验,杂志文章
doi:
更新日期:1997-09-01 00:00:00
abstract::Oncogene addiction is a phenomenon that the survival of cancer cells depends on an activated oncogene or inactivation of tumor suppressor gene, and is regarded as the 'Achilles heel' of the successful molecular targeted therapies in cancer. However, the role of oncogene addiction in gliomas has not been elucidated sys...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,评审
doi:10.1186/1756-9966-30-58
更新日期:2011-05-17 00:00:00
abstract::Pretreatment of ethyl acetate extract of Phellinus rimosus (Berk) Pilat protected cisplatin induced nephrotoxicity in mice. Single dose of the extract (25 and 50 mg/kg body weight) decreased cisplatin induced serum creatinine and urea levels. The cisplatin depleted renal antioxidant defence system, such as activity of...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2002-06-01 00:00:00
abstract:BACKGROUND:Next generation sequencing (NGS) is being increasingly applied for assisting cancer molecular diagnosis. However, it is still needed to validate NGS accuracy on detection of DNA alternations based on a large number of clinical samples, especially for DNA rearrangements and copy number variations (CNVs). This...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-017-0591-4
更新日期:2017-09-07 00:00:00
abstract::We evaluated the efficacy and toxicity profile of single-agent docetaxel administered in daily clinical practice at low-dose regimen in 37 pre-treated elderly patients with metastatic breast cancer previously exposed to chemotherapy. Docetaxel was employed by physician's preference according to a weekly (8 patients, 2...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 临床试验,杂志文章
doi:
更新日期:2005-03-01 00:00:00
abstract::A study of laryngeal carcinomas was performed in order to analyze (a) the expression of p53/p21, cyclin D1/cyclin E, p21/p27 (b) the relation of normal and abnormal protein expression, with the proliferation status, as determined by the expression of Ki67 and PCNA and (c) the correlation of our findings with prognosis...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2005-09-01 00:00:00
abstract:BACKGROUND:Pancreatic ductal adenocarcinoma is one of the leading causes of cancer-related death worldwide. Immune checkpoint blockade therapy, including anti-PD-1 and anti-PD-L1, is a new therapeutic strategy for cancer treatment but the monotherapy with PD-L1 inhibitors for pancreatic cancer is almost ineffective for...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-019-1044-z
更新日期:2019-02-01 00:00:00
abstract:BACKGROUND:Several targeted immunotherapies have recently showed significant advances in treatment of non-small cell lung cancer (NSCLC), including antibodies and inhibitors targeting programmed death-1 (PD-1) and its ligand (PD-L1). METHODS:Tumor tissue samples were prospectively collected from 183 patients with NSCL...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-019-1192-1
更新日期:2019-05-14 00:00:00
abstract:BACKGROUND:An External Quality Assessment (EQA) program was developed to investigate the state of the art of HER2 immunohistochemical determination in breast cancer (BC) in 16 Pathology Departments in the Lazio Region (Italy). This program was implemented through two specific steps to evaluate HER2 staining (step 1) an...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-32-58
更新日期:2013-08-21 00:00:00
abstract:BACKGROUND:This study aimed to analyze three-dimensional (3D) dosimetric data of conventional two-dimensional (2D) palliative spinal bone irradiation using different reference points and treatment plans with respect to the International Commission on Radiation Units and Measurements (ICRU) Report 50. METHODS:Forty-fiv...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-28-2
更新日期:2009-01-07 00:00:00
abstract:BACKGROUND:Long noncoding RNAs (lncRNAs) are considered critical regulators in cancers; however, the clinical significance and mechanisms of MAPKAPK5-AS1 (hereinafter referred to as MK5-AS1) in colorectal cancer (CRC) remain mostly unknown. METHODS:In this study, quantitative real-time PCR (qPCR) and western blotting ...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-020-01633-8
更新日期:2020-07-20 00:00:00
abstract::Gastric tissue was transplanted from the fundic and pyloric mucosa of 8-week old female F344 rats into the duodenum of males. Autopsy, 12 months after the operation, revealed grafts associated with persistent stones in the duodenum and/or calcification in the tissue. Pepsinogen positive chimeric glands with goblet cel...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2000-06-01 00:00:00
abstract::Tumor-infiltrating immune cells play a key role against cancer. However, malignant cells are able to evade the immune response and establish a very complex balance in which different immune subtypes may drive tumor progression, metastatization and resistance to therapy. New immunotherapeutic approaches aim at restorin...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,评审
doi:10.1186/s13046-020-01586-y
更新日期:2020-05-18 00:00:00
abstract::Preclinical research and ongoing clinical trials are validating epidermal growth factor receptor (EGFR) as a suitable molecular target in cancer therapy. Here we report the case of a 39-year-old non-smoking man with heavily pretreated stage IV bronchioloalveolar NSCLC who was treated with gefitinib ('Iressa', ZD1839) ...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2003-09-01 00:00:00
abstract::Cancer-associated fibroblasts (CAFs) plays an essential role in cancer cell growth, metabolism and immunoreaction. Autophagy is an intracellular self-degradative process that balances cell energy source and regulates tissue homeostasis. Targeting autophagy has gained interest with multiple preclinical and clinical tri...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,评审
doi:10.1186/s13046-019-1172-5
更新日期:2019-04-23 00:00:00
abstract:BACKGROUND:Anti-angiogenesis remains an attractive strategy for cancer therapy. Some anti-angiogenic reagents have bell-shape dose-response curves with higher than the effective doses yielding lower anti-angiogenic effects. In this study, two different types of anti-angiogenic reagents, a receptor tyrosine kinase inhib...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,收录出版
doi:10.1186/s13046-019-1324-7
更新日期:2019-08-28 00:00:00