Abstract:
:Metformin, an oral biguanide for the treatment of type II diabetes, has been shown to have anticancer effects in ovarian cancer. Energy starvation induced by metformin causes endoplasmic reticulum stress-mediated unfolded protein response (UPR) and autophagy. UPR and autophagy act as a survival or death mechanism in cells. In this study, we observed that metformin-induced apoptosis was relieved by autophagy and the PERK/eIF2α pathway in ovarian cancer cells, but not in peripheral blood mononuclear cells (PBMC) or 'normal' ovarian surface epithelial cells (OSE). Increased PARP cleavage and increased LC3B-II with ATG5-ATG12 complex suggested the induction of apoptosis and autophagy, respectively, in metformin-treated ovarian cancer cells. Accumulation of acidic vacuoles in the cytoplasm and downregulation of p62 further supported late-stage autophagy. Interestingly, metformin induced interdependent activation between autophagy and the UPR, especially the PERK/eIF2α pathway. Inhibition of autophagy-induced PERK inhibition, and vice versa, were demonstrated using small molecular inhibitors (PERK inhibitor I, GSK2606414; autophagy inhibitor, 3-MA, and BafA1). Moreover, autophagy and PERK activation protected ovarian cancer cells against metformin-induced apoptosis. Metformin treatment in the presence of inhibitors of PERK and autophagy, however, had no cytotoxic effects on OSE or PBMC. In conclusion, these results suggest that inhibition of autophagy and PERK can enhance the selective anticancer effects of metformin on ovarian cancer cells. © 2015 Wiley Periodicals, Inc.
journal_name
Mol Carcinogjournal_title
Molecular carcinogenesisauthors
Moon HS,Kim B,Gwak H,Suh DH,Song YSdoi
10.1002/mc.22284subject
Has Abstractpub_date
2016-04-01 00:00:00pages
346-56issue
4eissn
0899-1987issn
1098-2744journal_volume
55pub_type
杂志文章abstract::2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant mutagenic heterocyclic amine in cooked foods. Two mouse tumor cell lines, BMT11 and FM3A, were exposed to its proximate form, 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP). Fifty-six subclones of BMT11 and 39 subclones of ...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.2940090203
更新日期:1994-02-01 00:00:00
abstract::Malignant rhabdoid tumors (MRTs) are poorly differentiated pediatric cancers that arise in various anatomical locations and have a very poor outcome. The large majority of these malignancies are caused by loss of function of the SNF5/INI1 component of the SWI/SNF chromatin remodeling complex. However, the mechanism of...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.20568
更新日期:2009-12-01 00:00:00
abstract::Patients with advanced hepatocellular carcinoma (HCC) continue to have a dismal prognosis. Potential biomarkers to determine prognosis and select targeted therapies are urgently needed for patients with HCC. This study aimed to elucidate the role of UCK2 in HCC prognosis and tumor progression. We performed a screen of...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.22954
更新日期:2019-04-01 00:00:00
abstract::The restriction of energy intake has a profound inhibitory effect on carcinogenesis, yet the mechanism or mechanisms that account for this effect are unknown. In this experiment, the hypothesis tested was that energy restriction upregulates the expression of p27/kip1, a gene product associated with cell-cycle growth a...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/(sici)1098-2744(199904)24:4<241::aid-mc1>3
更新日期:1999-04-01 00:00:00
abstract::LEC (Long-Evans with a cinnamon-like coat color) rats develop hepatocellular carcinomas (HCCs) spontaneously. We examined mutations of codons 12, 13, and 61 of the Ha-ras, Ki-ras, and N-ras genes in four HCCs by the polymerase chain reaction (PCR)-single-stranded DNA direct sequencing method. No ras gene mutations wer...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.2940040405
更新日期:1991-01-01 00:00:00
abstract::FAM134B is an autophagy regulator of endoplasmic reticulum and acts as a cancer suppressor in colon cancer. However, the molecular signaling pathways by which FAM134B interacts within colon carcinogenesis is still unknown. Herein, this study aims to determine the interacting partners of FAM134B for the first time in c...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.22871
更新日期:2018-11-01 00:00:00
abstract::Bcl-x(L) is one of several antiapoptotic proteins regulated by signal transducer and activator of transcription 3 (Stat3). We have recently shown that Stat3 is required for chemically induced and ultraviolet B (UVB)-induced skin carcinogenesis. In this study, the functional role of Bcl-x(L) in skin carcinogenesis was ...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.20527
更新日期:2009-10-01 00:00:00
abstract::The ubiquitin-proteasome pathway is fundamental to synchronized continuation of many cellular processes, for example, cell-cycle progression, stress response, and cell differentiation. Recent studies have shown that the ubiquitin-proteasome pathway functions in the regulation of nucleotide excision repair (NER) in yea...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.20065
更新日期:2005-01-01 00:00:00
abstract::Estrogen is thought to be an important etiologic agent in endometrial and breast cancers. However, the mechanism or mechanisms by which estrogen acts as a hormonal carcinogen are not well understood. We hypothesize that in response to chronic exposure to estrogens, human endometrial stromal fibroblasts (ESF) produce f...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/(sici)1098-2744(199812)23:4<217::aid-mc4>3
更新日期:1998-12-01 00:00:00
abstract::Heterocyclic amines present in cooked foods are known to produce colon tumors in F344 rats at a high incidence, indicating the possibility of involvement of ras gene activation in colon carcinogenesis in rats as in humans. We examined mutations at codons 12, 13, and 61 of the Ki-ras, Ha-ras, and N-ras genes by polymer...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.2940080110
更新日期:1993-01-01 00:00:00
abstract::Expression of the tumor suppressor deleted in liver cancer-1 (DLC-1) is lost in non-small cell lung (NSCLC) and other human carcinomas, and ectopic DLC-1 expression dramatically reduces proliferation and tumorigenicity. DLC-1 is a multi-domain protein that includes a Rho GTPase activating protein (RhoGAP) domain which...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.20389
更新日期:2008-05-01 00:00:00
abstract::Transforming growth factor-beta (TGF-beta) is a growth modulator that inhibits the proliferation of many epithelial cells through interaction with its receptors, the type I and type II receptors (TGF-beta RI and RII) by activating their serine/threonine kinase activities. Loss of growth inhibition by TGF-beta is thoug...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/(sici)1098-2744(199805)22:1<46::aid-mc6>3.
更新日期:1998-05-01 00:00:00
abstract::Xiphophorus fish have been the subject of intensive genetic research for more than 60 yr, primarily because of the availability of a number of interspecific hybrids that are malignant melanoma models with apparently simple oncogene and tumor suppressor gene determinants. The gene map of Xiphophorus is one of the most ...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/(sici)1098-2744(199807)22:3<150::aid-mc2>3
更新日期:1998-07-01 00:00:00
abstract::Composition of extracellular matrix (ECM) is crucial to the establishment and maintenance of epithelial apical-basolateral polarity. Increased ECM rigidity caused by deposition of fibrillar collagen, for example, collagen type I (Col-1), promotes loss of epithelial polarity and tumor progression. microRNAs are small n...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.20742
更新日期:2011-07-01 00:00:00
abstract::Using relatively primitive tools in the 1920s, Otto Warburg demonstrated that tumor cells show an increased dependence on glycolysis to meet their energy needs, regardless of whether they were well-oxygenated or not. High rates of glucose uptake, fueling glycolysis, are now used clinically to identify cancer cells. Ho...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章,评审
doi:10.1002/mc.21863
更新日期:2013-05-01 00:00:00
abstract::Reflux of acidic gastric contents and bile acids into the lower esophagus has been identified to have a central role in esophageal malignancy and is reported to upregulate caudal-related homologue 2 (CDX2), a regulatory gene involved in embryonic development and axial patterning of the alimentary tract. The aim of thi...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.20549
更新日期:2009-10-01 00:00:00
abstract::An allelotype analysis of lung tumors in mouse hybrids was conducted to identify common regions of allelic loss. By using 50 informative genetic markers, the autosomes of 36 (A/J x C3H/HeJ) F1 adenocarcinomas were examined. Additional adenocarcinomas from as many as 72 (C3H/HeJ x A/J) F1 and 15 (BALB/cJ x DBA/2J) F1 h...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/(SICI)1098-2744(199606)16:2<83::AID-MC4>3.
更新日期:1996-06-01 00:00:00
abstract::Previous studies have established the in vivo bioavailability and efficacious dosages of phenylbutyl isoselenocyanate (ISC-4), a selenium-substituted isothiocyanate, against mouse xenograft models of human melanoma and colorectal cancer. To explore its potential attributes against prostate cancer, we treated human LNC...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.22825
更新日期:2018-08-01 00:00:00
abstract::Withaferin A (WA), a natural product derived from Withania somnifera, has been used in traditional oriental medicines to treat neurological disorders. Recent studies have demonstrated that this compound may have a potential for cancer treatment and a clinical trial has been launched to test WA in treating melanoma. He...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.22423
更新日期:2016-11-01 00:00:00
abstract::Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 g...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.22476
更新日期:2017-01-01 00:00:00
abstract::Diet-derived butyrate, a histone deacetylase inhibitor (HDI), decreases proliferation and increases apoptosis in colorectal cancer (CRC) cells via epigenetic changes in gene expression. Other HDIs such as suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) have similar effects. This study examined the role...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.21879
更新日期:2013-06-01 00:00:00
abstract::To investigate the effect of tumor-associated macrophages on the in vivo growth properties of cervical carcinoma cells, tumorigenic human papilloma virus (HPV) 18-positive HeLa cells were transfected with an expression vector harboring the cDNA for the macrophage chemoattractant protein-1 JE (MCP-1). Although the endo...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.2940140307
更新日期:1995-11-01 00:00:00
abstract::The cellular senescence program is controlled by multiple genetic pathways, one of which involves the regulation of telomerase and telomere shortening. The introduction of a normal human chromosome 3 into the human renal cell carcinoma cell line RCC23 caused repression of telomerase activity, progressive shortening of...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/(sici)1098-2744(199806)22:2<65::aid-mc1>3.
更新日期:1998-06-01 00:00:00
abstract::There is an unmet need to develop new agents or strategies against therapy resistant pancreatic cancer (PanCA). Recent studies from our laboratory showed that STAT3 negatively regulates NF-κB and that inhibition of this crosstalk using Nexrutine® (Nx) reduces transcriptional activity of COX-2. Inhibition of these mole...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.22503
更新日期:2017-02-01 00:00:00
abstract::Both ultraviolet irradiation and oxidation of DNA produce a variety of pyrimidine base damages. A human endonuclease recognizes such altered bases on these DNA substrates. This human endonuclease incises ultraviolet-irradiated DNA exclusively at sites of photochemically modified cytosines. The precise sites of incisio...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.2940020404
更新日期:1989-01-01 00:00:00
abstract::Cyclooxygenase-2 (COX-2) is one of the isoforms of cyclooxygenase, a rate-limiting enzyme in the arachidonic acid cascade. COX-2 protein expression is highly induced by numerous factors and it has been reportedly overexpressed in various human malignancies. Although anti-tumorigenic effects of COX-2 inhibitors have be...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.22458
更新日期:2016-12-01 00:00:00
abstract::The tumor suppressor p27, which is a member of the Cip/Kip family of Cyclin-dependent kinase inhibitory proteins (CKIs), controls anti-proliferative events. The post-translational addition of O-GlcNAc to p27 occurs in HEK293T and HCC (hepatocellular carcinoma) cell lines, and we identified Ser2, Ser106, Ser110, Thr157...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.22490
更新日期:2017-01-01 00:00:00
abstract::The WW domain-containing oxidoreductase (WWOX) gene is an identified tumor suppressor gene, of which several single nucleotide polymorphisms have been reported to contribute to cancer susceptibility. We hypothesized that genetic variations in WWOX are associated with lung cancer risk. In two independent case-control s...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.21934
更新日期:2013-11-01 00:00:00
abstract::O6-Alkylguanine is a major toxic, mutagenic, and carcinogenic lesion in cellular DNA that is repaired by O6-alkylguanine-DNA alkyltransferase (ATase). The expression of this gene is directly related to the cellular sensitivity of alkylating agents, with levels of this protein varying widely among human organs, tumors,...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.2940120309
更新日期:1995-03-01 00:00:00
abstract::Flavonoids are the most investigated phytochemicals due to their pharmacological and therapeutic activities. Their ability to chelate with metal ions has resulted in the emergence of a new category of molecules with a broader spectrum of pharmacological activities. In this study, the ruthenium quercetin complex has be...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.22792
更新日期:2018-06-01 00:00:00