Abstract:
BACKGROUND:Pancreas ductal adenocarcinoma (PDAC) has the most dismal prognosis among all human cancers since it is highly resistant to chemotherapy, radiotherapy and immunotherapy. The anticipated consequence of all therapies is induction of tumor apoptosis. The highly resistance nature of PDACs to all therapies suggests that the intrinsic tumor cell factors, likely the deregulated apoptosis pathway, are key mechanisms underlying PDAC non-response to these therapies, rather than the therapeutic agents themselves. The aim of this study is to test the hypothesis that epigenetic dysregulation of apoptosis mediators underlies PDAC resistance to gemcitabine, the standard chemotherapy for human PDAC. METHODS:PDAC cells were analyzed for apoptosis sensitivity in the presence of a selective epigenetic inhibitor. The epigenetic regulation of apoptosis regulators was determined by Western Blotting and quantitative PCR. The specific epigenetic modification of apoptosis regulator promoter chromatin was determined by chromatin immunoprecipitation in PDAC cells. RESULTS:Inhibition of histone methyltransferase (HMTase) by a selective HMTase inhibitor, verticillin A, significantly increased human PDAC cell sensitivity to gemcitabine-induced growth suppression. Verticillin A treatment decreased FLIP, Mcl-1, Bcl-x and increased Bak, Bax and Bim protein level in the tumor cells, resulting in activation of caspases, elevated cytochrome C release and increased apoptosis as determined by upregulated PARP cleavage in tumor cells. Analysis of human PDAC specimens indicated that the expression levels of anti-apoptotic mediators Bcl-x, Mcl-1, and FLIP were significantly higher, whereas the expression levels of pro-apoptotic mediators Bim, Bak and Bax were dramatically lower in human PDAC tissues as compared to normal pancreas. Verticillin A downregulated H3K4me3 levels at the BCL2L1, CFLAR and MCL-1 promoter to decrease Bcl-x, FLIP and Mcl-1 expression level, and inhibited H3K9me3 levels at the BAK1, BAX and BCL2L11 promoter to upregulate Bak, Bax and Bim expression level. CONCLUSION:We determined that PDAC cells use H3K4me3 to activate Bcl-x, FLIP and Mcl-1, and H3K9me3 to silence Bak, Bax and Bim to acquire an apoptosis-resistant phenotype. Therefore, selective inhibition of H3K4me3 and H3K9me3 is potentially an effective approach to overcome PDAC cells resistance to gemcitabine.
journal_name
BMC Cancerjournal_title
BMC cancerauthors
Lu C,Yang D,Sabbatini ME,Colby AH,Grinstaff MW,Oberlies NH,Pearce C,Liu Kdoi
10.1186/s12885-018-4061-ysubject
Has Abstractpub_date
2018-02-06 00:00:00pages
149issue
1issn
1471-2407pii
10.1186/s12885-018-4061-yjournal_volume
18pub_type
杂志文章相关文献
BMC CANCER文献大全abstract:BACKGROUND:The incidence and survival of melanoma are increasing, but little is known about its long-term health effects in adult survivors. METHODS:A health survey was available from 996 melanoma survivors (577 treated with surgery alone, and 391 with combined treatments). Their medical/physiologic and psychosocial r...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-6-95
更新日期:2006-04-18 00:00:00
abstract:BACKGROUND:First-line treatment with FOLFOXIRI plus bevacizumab (BEV) is highly effective and regarded as one of the standards-of-care for patients with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea as side effects. AXEPT, an Asian phase III study, showed that modified CAPI...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/s12885-020-07186-5
更新日期:2020-07-23 00:00:00
abstract:BACKGROUND:Despite introduction of effective chemotherapy protocols, it has remained uncertain, if patients with colorectal cancer (CRC) liver metastases should receive adjuvant therapy. Clinical or molecular predictors may help to select patients at high risk for disease recurrence and death who obtain a survival adva...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-14-174
更新日期:2014-03-11 00:00:00
abstract:BACKGROUND:Cancer patients routinely develop symptoms consistent with profound circadian disruption, which causes circadian disruption diminished quality of life. This study was initiated to determine the relationship between the severity of potentially remediable cancer-associated circadian disruption and quality of l...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-11-193
更新日期:2011-05-23 00:00:00
abstract:BACKGROUND:Muscle invasive bladder cancer (MIBC) is often lethal and non-MIBC (NMIBC) can recur and progress, yet prognostic markers are currently inadequate. SAM68, a member of RNA-binding proteins, has been reported to contribute to progression of other cancers. The aim of this study is to investigate the potential u...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/s12885-015-1367-x
更新日期:2015-05-06 00:00:00
abstract:BACKGROUND:Gambogic acid (GA) is a major active ingredient of gamboge, a widely used traditional Chinese medicine that has been reported to be a potent cytotoxic agent against some malignant tumors. Many studies have shown that the NF-kappa B signaling pathway plays an important role in anti-apoptosis and the drug resi...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-9-343
更新日期:2009-09-25 00:00:00
abstract:BACKGROUND:Colorectal-cancer is a leading cause of cancer death in the United States, and Latinos have particularly low rates of screening. Strategies and Opportunities to STOP Colon Cancer in Priority Populations (STOP CRC) is a partnership among two research institutions and a network of safety net clinics to promote...
journal_title:BMC cancer
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1186/1471-2407-14-55
更新日期:2014-02-26 00:00:00
abstract:BACKGROUND:No scientific consensus has been reached on whether active tobacco smoking causes breast cancer. We examine the association between active smoking and breast cancer risk in Denmark, which has some of the highest smoking and breast cancer rates in women worldwide. METHODS:We used the data from a nationwide D...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/s12885-017-3546-4
更新日期:2017-08-22 00:00:00
abstract:BACKGROUND:High grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogran...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/s12885-019-6498-z
更新日期:2020-01-10 00:00:00
abstract:BACKGROUND:Cancers of unknown primary origin (CUPs) are reported to be the 3-4th most common causes of cancer death. Recent years have seen advances in mutational analysis and genomics profiling. These advances could improve accuracy of diagnosis of CUPs and might improve the prognosis of patients with CUPs. CASE PRES...
journal_title:BMC cancer
pub_type: 杂志文章,评审
doi:10.1186/s12885-019-5277-1
更新日期:2019-01-11 00:00:00
abstract:BACKGROUND:Ectopic TSH-secreting pituitary adenoma (TSH-oma) is a very unusual disorder. To date, there are only four cases reported. It is difficult to distinguish ectopic cases from both regular TSH-omas and resistance to thyroid hormone (RTH). CASE PRESENTATION:A newly identified case of ectopic TSH-oma arising fro...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-14-544
更新日期:2014-07-28 00:00:00
abstract:BACKGROUND:Our aim was to investigate the value of serum squamous cell carcinoma (SCC) antigen levels in predicting chemosensitivity, lymph node metastasis, as well as prognosis in patients with cervical squamous cell carcinoma who received neoadjuvant chemotherapy (NACT). METHODS:This retrospective study enrolled 103...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/s12885-020-06934-x
更新日期:2020-05-14 00:00:00
abstract:BACKGROUND:About 5-10% of breast cancer is due to inherited disease predisposition. Many previously identified susceptibility factors are involved in the maintenance of genomic integrity. AATF plays an important role in the regulation of gene transcription and cell proliferation. It induces apoptosis by associating wit...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-9-457
更新日期:2009-12-21 00:00:00
abstract:BACKGROUND:Tobacco smoke exposure may be associated with increased breast cancer risk, although the evidence supporting the association is inconclusive. We conducted a case-control study in Delaware, incorporating detailed exposure assessment for active and secondhand smoke at home and in the workplace. METHODS:Primar...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-8-157
更新日期:2008-06-02 00:00:00
abstract:BACKGROUND:The association between immune-related adverse events (irAEs) and survival outcomes in patients with advanced melanoma receiving therapy with immune checkpoint inhibitors (ICIs) has not been well established, particularly in Asian melanoma. METHODS:We retrospectively reviewed 49 melanoma patients undergoing...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/s12885-020-07508-7
更新日期:2020-10-21 00:00:00
abstract:BACKGROUND:Protein secretion by mammary cells results in autocrine and paracrine signaling that defines cell growth, migration and the extracellular environment. Even so, we have a limited understanding of the cellular processes that regulate protein secretion. METHODS:In this study, we utilize human epithelial mammar...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-11-69
更新日期:2011-02-14 00:00:00
abstract:BACKGROUND:Metastatic renal cell carcinoma (mRCC) had been a chemo-refractory disease, but recent advances in multiple kinase inhibitors such as sunitinib have dramatically changed the clinical course of mRCC. Sunitinib is used for mRCC chemotherapy based on the favorable results of a recent clinical trial, but specifi...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/s12885-015-1443-2
更新日期:2015-05-22 00:00:00
abstract:BACKGROUND:Recent randomized controlled trials comparing neoadjuvant chemoradiation plus surgery or perioperative chemotherapy plus surgery with surgery alone showed significant survival benefits for combined modality treatment of patients with localized esophageal adenocarcinoma. However, head-to-head comparisons of n...
journal_title:BMC cancer
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1186/s12885-016-2564-y
更新日期:2016-07-19 00:00:00
abstract:BACKGROUND:Alteration in gut microbiota has been recently linked with childhood leukemia and the use of chemotherapy. Whether the perturbed microbiota community is restored after disease remission and cessation of cancer treatment has not been evaluated. This study examines the chronological changes of gut microbiota i...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/s12885-020-6654-5
更新日期:2020-02-24 00:00:00
abstract:BACKGROUND:There is a large body of evidence which suggests that bile acids increase the risk of colon cancer and act as tumor promoters, however, the mechanism(s) of bile acids mediated tumorigenesis is not clear. Previously we showed that deoxycholic acid (DCA), a tumorogenic bile acid, and ursodeoxycholic acid (UDCA...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-6-219
更新日期:2006-09-01 00:00:00
abstract:BACKGROUND:As one of the malignant tumors most often affecting children and young adults, Ewing sarcoma (ES) is characterized by early metastasis contributing to unfavorable prognosis. However, the molecular mechanisms responsible for ES metastasis remain poorly understood. In this study, we aimed to explore whether Wn...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-12-480
更新日期:2012-10-18 00:00:00
abstract:BACKGROUND:Prostate cancer is the second leading cause of male cancer death in developed countries. Although the role of angiogenesis in its progression is well established, the efficacy of anti-angiogenic therapy is not clearly proved. Whether this could depend on differential responses between tumor and normal endoth...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-14-939
更新日期:2014-12-12 00:00:00
abstract:BACKGROUND:Breast cancer is the leading cause of cancer mortality in women worldwide. Therefore, it is of great significance to identify the biological mechanism of tumorigenesis and explore the development of breast cancer to achieve a better prognosis for individuals suffering from breast cancer. MicroRNAs (miRNAs) h...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/s12885-020-07395-y
更新日期:2020-10-02 00:00:00
abstract:BACKGROUND:Programmed cell death 1 (PD1) inhibitors have recently shown promising anti-cancer effects in a number of solid tumor types. A predictive biomarker to this class of drugs has not been clearly identified; however, overexpression of the PD1 ligand (PD-L1) has shown particular promise in lung adenocarcinoma. In...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/s12885-017-3634-5
更新日期:2017-09-05 00:00:00
abstract:BACKGROUND:Orthodenticle homeobox 1 (OTX1) is a transcription factor that plays an important role in various human cancers. However, the function of OTX1 in laryngeal squamous cell carcinoma (LSCC) is largely unknown. We aimed to explore the roles of OTX1 in LSCC and its possible molecular mechanism. METHODS:The expre...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/s12885-020-07279-1
更新日期:2020-08-24 00:00:00
abstract:BACKGROUND:Resistance to 5-fluorouracil (5-FU) in patients with colorectal cancer prevents effective treatment and leads to unnecessary and burdensome chemotherapy. Therefore, prediction of 5-FU resistance is imperative. METHODS:To identify the proteins linked to 5-FU resistance, two-dimensional gel electrophoresis-ba...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-14-160
更新日期:2014-03-06 00:00:00
abstract:BACKGROUND:Activation of caspase-9 in response to treatment with cytotoxic drugs is inhibited in NSCLC cells, which may contribute to the clinical resistance to chemotherapy shown in this type of tumor. The aim of the present study was to investigate the mechanism of caspase-9 inhibition, with a focus on a possible rol...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-6-166
更新日期:2006-06-23 00:00:00
abstract:BACKGROUND:Sorafenib is an orally active multikinase tyrosine kinase inhibitor (TKI) that targets B-type Raf kinase (BRAF), vascular endothelial growth factor receptors (VEGFR) 1 and 2, and rearranged during transfection (RET), inducing anti-angiogenic and pro-apoptotic actions in a wide range of solid tumors. A side e...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/s12885-016-2060-4
更新日期:2016-01-19 00:00:00
abstract:BACKGROUND:Although radical surgery remains the cornerstone of cure in resectable gastric cancer, survival remains poor. Current evidence-based (neo)adjuvant strategies have shown to improve outcome, including perioperative chemotherapy, postoperative chemoradiotherapy and postoperative chemotherapy. However, these reg...
journal_title:BMC cancer
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1186/s12885-018-4770-2
更新日期:2018-09-10 00:00:00
abstract:BACKGROUND:The serine-threonine kinase AKT1 plays essential roles during normal mammary gland development as well as the initiation and progression of breast cancer. AKT1 is generally considered a ubiquitously expressed gene, and its persistent activation is transcriptionally controlled by regulatory elements character...
journal_title:BMC cancer
pub_type: 杂志文章
doi:10.1186/1471-2407-14-195
更新日期:2014-03-15 00:00:00