Search tips
Search criteria

Results 1-11 (11)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
author:("Nie, daota")
1.  Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters 
Biochemical Pharmacology  2012;83(8):1112-1126.
Chemotherapy is one of the three most common treatment modalities for cancer. However, its efficacy is limited by multidrug resistant cancer cells. Drug metabolizing enzymes (DMEs) and efflux transporters promote the metabolism, elimination, and detoxification of chemotherapeutic agents. Consequently, elevated levels of DMEs and efflux transporters reduce the therapeutic effectiveness of chemotheraputics and, often, lead to treatment failure. Nuclear receptors, especially pregnane X receptor (PXR, NR1I2) and constitutive androstane activated receptor (CAR, NR1I3), are increasingly recognized for their role in xenobiotic metabolism and clearance as well as their role in the development of multidrug resistance (MDR) during chemotherapy. Promiscuous xenobiotic receptors, including PXR and CAR, govern the inducible expressions of a broad spectrum of target genes that encode phase I DMEs, phase II DMEs, and efflux transporters. Recent studies conducted by a number of groups, including ours, have revealed that PXR and CAR play pivotal roles in the development of MDR in various human carcinomas, including prostate, colon, ovarian, and esophageal squamous cell carcinomas. Accordingly, PXR/CAR expression levels and/or activation statuses may predict prognosis and identify the risk of drug resistance in patients subjected to chemotherapy. Further, PXR/CAR antagonists, when used in combination with existing chemotherapeutics that activate PXR/CAR, are feasible and promising options that could be utilized to overcome or, at least, attenuate MDR in cancer cells.
PMCID: PMC3339266  PMID: 22326308
2.  Non-steroid anti-inflammatory drugs, prostaglandins, and cancer 
Cell & Bioscience  2013;3:8.
Fatty acids are involved in multiple pathways and play a pivotal role in health. Eicosanoids, derived from arachidonic acid, have received extensive attention in the field of cancer research. Following release from the phospholipid membrane, arachidonic acid can be metabolized into different classes of eicosanoids through cyclooxygenases, lipoxygenases, or p450 epoxygenase pathways. Non-steroid anti-inflammatory drugs (NSAIDs) are widely consumed as analgesics to relieve minor aches and pains, as antipyretics to reduce fever, and as anti-inflammatory medications. Most NSAIDs are nonselective inhibitors of cyclooxygenases, the rate limiting enzymes in the formation of prostaglandins. Long term use of some NSAIDs has been linked with reduced incidence and mortality in many cancers. In this review, we appraise the biological activities of prostanoids and their cognate receptors in the context of cancer biology. The existing literature supports that these lipid mediators are involved to a great extent in the occurrence and progression of cancer.
PMCID: PMC3599181  PMID: 23388178
Experimental cell research  2010;316(10):1706-1715.
12-lipoxygenase, an arachidonic acid metabolizing enzyme of the lipoxygenase pathway, has been implicated as a major factor in promoting prostate cancer progression and metastasis. The ability of 12-LOX to aggravate the disease was linked to its proangiogenic role. Recent studies clearly demonstrated that 12-LOX enhances the expression and secretion of the angiogenic factor, vascular endothelial growth factor (VEGF) thus providing a direct link between this enzyme and its angiogenic properties. In the present study we have investigated the relationship between 12-LOX and hypoxia inducible factor-1α (HIF-1α), a transcription factor involved in the regulation of VEGF expression under hypoxic conditions in solid tumors. Our findings have revealed that HIF-1 is one of the target transcription factors regulated by 12-LOX and 12(S)-HETE, in hypoxic tumor cells of the prostate. Regulation of HIF-1α by 12-LOX adds to the complexity of pathways mediated by this enzyme in promoting prostate cancer angiogenesis and metastasis. We have evidence that 12-LOX increases the protein level, mRNA, and functional activity of HIF-1α under hypoxic conditions, one of the mechanisms by which it upregulates VEGF secretion and activity.
PMCID: PMC3420817  PMID: 20303950
12-Lipoxygenase; Hypoxia Inducible Factor-1α (HIF-1α); angiogenesis; prostate cancer; hypoxia
4.  PPARgamma, Bioactive Lipids, and Cancer Progression 
In this article we review the evolution of cancer research involving PPARgamma, including mechanisms, target genes, and clinical applications. For the last thirteen years, the effects of PPARgamma activity on tumor biology have been studied intensely. Most of this research has focused upon the potential for employing agonists of this nuclear receptor in cancer treatment. As a monotherapy such agonists have shown little success in clinical trials, while they have shown promise as components of combination treatments both in culture and in animal models. Other investigations have explored a possible role for PPARgamma as a tumor suppressor, and as an inducer of differentiation of cancer stem cells. Whereas early studies have yielded variable conclusions regarding the prevalence of PPARgamma mutations in cancer, the protein level of this receptor has been more recently identified as a significant prognostic marker. We predict that indicators of PPARgamma activity may also serve as predictive markers for tailoring treatments.
PMCID: PMC3409468  PMID: 22201838
PPARgamma; cancer; thiazolidinediones; lipoxygenases; COX
5.  Growth factors in tumor microenvironment 
Tumor microenvironment plays a critical role in tumor initiation and progression. Components in the microenvironment can modulate the growth of tumor cells, their ability to progress and metastasize. A major venue of communication between tumor cells and their microenvironment is through polypeptide growth factors and receptors for these growth factors. This article discusses three major classes of growth-stimulatory polypeptide growth factors and receptors for these growth factors. It also discusses how deregulation of these growth factors or their receptors can drive malignant transformation and progression.
PMCID: PMC3409472  PMID: 20036812
Tumor microenvironment; growth factor; EGFR; FGF; PDGF
6.  Regulation of drug resistance by human pregnane X receptor in breast cancer 
Cancer biology & therapy  2009;8(13):1265-1272.
Drug resistance is a significant barrier to an effective treatment of breast cancer. Human pregnane X receptor (hPXR), an orphan nuclear receptor known for its activation by many important clinical drugs, is a major transcription factor of drug metabolism enzymes (DMEs), such as cytochrome P450 3A4 (CYP3A4), and efflux transporters such as multi-drug resistance gene (MDR1). hPXR has been detected in human breast cancers but its role in responses of cancers toward drugs remains unknown. In this study, hPXR expression was confirmed in breast cancer cell lines and in normal and cancerous human breast specimens. Preactivation of hPXR by SR12813 in MDA-MB-231 cells led to an increased resistance to Taxol at concentrations of 20 and 50 nmol/L. A significant increase in resistance toward tamoxifen was also observed in MCF-7 with hPXR preactivation. Activation of hPXR led to an increased expression of CYP3A4 and MDR1, two possible mediators for hPXR-mediated drug resistance in breast cancers. Furthermore, knockdown of hPXR via small hairpin RNA (shRNA) sensitized MDA-MB-231 and MCF-7 cells to the treatment of Taxol, vinblastine or tamoxifen. The reduction in resistance of hPXR knockdown cells was further confirmed by reduced colony formation under the pressure of cancer treatment drugs. Taken together, our data suggest a potential role of hPXR in breast cancer resistance to drug treatments.
PMCID: PMC3392171  PMID: 19746521
pregnane X receptor; steroid and xenobiotic receptor; breast cancer; chemotherapy; drug resistance; taxol; tamoxifen; vinblastine; drug metabolism enzymes; transcriptional regulation
7.  Short-chain fatty acids induced autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death 
Cell death and differentiation  2010;18(4):602-618.
Short-chain fatty acids are the major by-products of bacterial fermentation of undigested dietary fibers in human large intestine. SCFAs, mostly propionate and butyrate, inhibit proliferation and induce apoptosis in colon cancer cells, but clinical trials had mixed results regarding the anti-tumor activities of SCFAs. Herein we demonstrate that propionate and butyrate induced autophagy in human colon cancer cells to dampen apoptosis whereas inhibition of autophagy potentiated SCFA induced apoptosis. Colon cancer cells, after propionate treatment, exhibited extensive characteristics of autophagic proteolysis: increased LC3-I to LC3-II conversion, acidic vesicular organelle development and reduced p62/SQSTM1 expression. Propionate-induced autophagy was associated with decreased mTOR activity and enhanced AMP kinase activity. The elevated AMPKα phosphorylation was associated with cellular ATP depletion and overproduction of reactive oxygen species due to mitochondrial dysfunction involving the induction of MPT and loss of Δψ. In this context, mitochondria biogenesis was initiated to recover cellular energy homeostasis. Importantly, when autophagy was prevented either pharmacologically (3-MA or chloroquine) or genetically (knockdown of ATG5 or ATG7), the colon cancer cells became sensitized toward propionate induced apoptosis through activation of caspase 7 and its downstream effector caspase-3. The observations indicate that propionate-triggered autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death, whereas application of an autophagy inhibitor (Chloroquine) is expected to enhance the therapeutic efficacy of SCFAs in inducing colon tumor cell apoptosis.
PMCID: PMC3020988  PMID: 20930850
Short-chain fatty acids; autophagy; apoptosis; mitochondrial; colon cancer
8.  Promotion of tumor development in prostate cancer by progerin 
Progerin is a truncated form of lamin A. It is identified in patients with Hutchinson-Gilford progeria syndrome (HGPS), a disease characterized by accelerated aging. The contribution of progerin toward aging has been shown to be related to increased DNA damages. Since aging is one major risk factor for carcinogenesis, and genomic instability is a hallmark of malignant cancers, we investigated the expression of progerin in human cancer cells, and whether its expression contributes to carcinogenesis. Using RT-PCR and Western blotting, we detected the expression of progerin in prostate PC-3, DU145 and LNCaP cells at mRNA and protein levels. Ectopic progerin expression did not cause cellular senescence in PC-3 or MCF7 cells. PC-3 cells progerin transfectants were sensitized to DNA damage agent camptothecin (CPT); and persistent DNA damage responses were observed, which might be caused by progerin induced defective DNA damage repair. In addition, progerin transfectants were more tumorigenic in vivo than vector control cells. Our study for the first time describes the expression of progerin in a number of human cancer cell lines and its contributory role in tumorigenesis.
PMCID: PMC3003644  PMID: 21106101
9.  hCLCA2 is a p53-inducible inhibitor of breast cancer cell proliferation 
Cancer research  2009;69(16):6624-6632.
hCLCA2 is frequently downregulated in breast cancer and is a candidate tumor suppressor gene. We show here that the hCLCA2 gene is strongly induced by p53 in response to DNA damage. Adenoviral expression of p53 induces hCLCA2 in a variety of breast cell lines. Further, we find that p53 binds to consensus elements in the hCLCA2 promoter and mutation of these sites abolishes p53-responsiveness and induction by DNA damage. Adenoviral transduction of hCLCA2 into immortalized cells induces p53, CDK inhibitors p21 and p27, and cell cycle arrest by 24 hours, and caspase induction and apoptosis by 40 hours post-infection. Transduction of the malignant tumor cell line BT549 on the other hand does not induce p53, p21, or p27 but instead induces apoptosis directly and more rapidly. Knockout and knockdown studies indicate that growth inhibition and apoptosis are signaled via multiple pathways. Conversely, suppression of hCLCA2 by RNA interference enhances proliferation of MCF10A and reduces sensitivity to doxorubicin. Gene expression profiles indicate that hCLCA2 levels are strongly predictive of tumor cell sensitivity to doxorubicin and other chemotherapeutics. Because certain Cl- channels are proposed to promote apoptosis by reducing intracellular pH, we tested whether, and established that, hCLCA2 enhances Cl- current in breast cancer cells and reduces pH to ∼6.7. These results reveal hCLCA2 as a novel p53-inducible growth inhibitor, explain how its downregulation confers a survival advantage to tumor cells, and suggest both prognostic and therapeutic applications.
PMCID: PMC2745301  PMID: 19654313
DNA damage; p53; chloride channel regulator; breast cancer; tumor suppressor; intracellular acidification
10.  Downregulation of Vascular Endothelial Growth Factor and Induction of Tumor Dormancy by 15-lipoxygenase-2 in Prostate Cancer 
The enzyme 15-lipoxygenase-2 (15-LOX-2) utilizes arachidonic acid, a polyunsaturated fatty acid, to synthesize 15(S)-hydroxyeicosatetraenoic acid (HETE). Abundantly expressed in normal prostate epithelium but frequently suppressed in the cancerous tissues, 15-LOX-2 has been suggested as a functional suppressor of prostate cancer, but the mechanism(s) involved remains unknown. To study the functional role of 15-LOX-2 in prostate cancer, we expressed 15-LOX-2 as a fusion protein with GFP in DU145 and PC-3 cells and found that 15-LOX-2 increased cell cycle arrest at G0/G1 phase. When injected into athymic nu/nu mice, prostate cancer cells with 15-LOX-2 expression could still form palpable tumors without significant changes in tumorigenicity. But, the tumors with 15-LOX-2 expression grew significantly slower than those derived from vector controls and were kept dormant for a long period of time. Histological evaluation revealed an increase in cell death in tumors derived from prostate cancer cells with 15-LOX-2 expression, while in vitro cell culture conditions, no such increase in apoptosis was observed. Further studies found that the expression of vascular endothelial growth factor A (VEGF-A) was significantly reduced in prostate cancer cells with 15-LOX-2 expression restored. Our studies suggest that 15-LOX-2 suppresses VEGF gene expression and sustains tumor dormancy in prostate cancer. Loss of 15-LOX-2 functionalities, therefore, represents a key step for prostate cancer cells to exit from dormancy and embark on malignant progression in vivo.
PMCID: PMC2913418  PMID: 19089921
tumor dormancy; angiogenesis; lipoxygenase; prostate cancer; VEGF
11.  Impairment of mitochondrial respiration in mouse fibroblasts by oncogenic H-RASQ6IL 
Cancer biology & therapy  2010;9(2):122-133.
A common metabolic change in cancer is the acquisition of glycolytic phenotypes. Increased expression of glycolytic enzymes is considered as one contributing factor. The role of mitochondrial defects in acquisition of glycolytic phenotypes has been postulated but remains controversial. Here we show that functional defects in mitochondrial respiration could be induced by oncogenic H-RasQ61L transformation, even though the mitochondrial contents or mass was not reduced in the transformed cells. First, mitochondrial respiration, as measured by mitochondrial oxygen consumption, was suppressed in NIH-3T3 cells transformed with H-RasQ61L. Second, oligomycin or rotenone did not reduce the cellular ATP levels in the H-RasQ61L transformed cells, suggesting a diminished role of mitochondrial respiration in the cellular energy metabolism. Third, inhibition of glycolysis with iodoacetic acid reduced ATP levels at a much faster rate in H-RasQ61L transformed cells than in the vector control cells. The reduction of cellular ATP levels was reversed by exogenously added pyruvate in the vector control cells but not in H-RasQ61L transformed cells. Finally when compared to the HRasQ61L transformed cells, the vector control cells had increased resistance toward glucose deprivation. The increased resistance was dependent on mitochondrial oxidative phosphorylation since rotenone or oligomycin abolished the increased survival of the vector control cells under glucose deprivation. The results also suggest an inability of the H-RasQ61L transformed cells to reactivate mitochondrial respiration under glucose deprivation. Taken together, the data suggest that mitochondrial respiration can be impaired during transformation of NIH-3T3 cells by oncogeneic H-RasQ61L.
PMCID: PMC2909490  PMID: 19923925
Ras; mitochondrial respiration; glycolysis; Electron transport chain; complex IV; transformation; cellular energy metabolism; ATP

Results 1-11 (11)