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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of t(4;14)(p16.3;q32.3) in multiple myeloma cells results in dysregulated expression of the fibroblast growth factor receptor 3 (FGFR3). FGFR3 acts as an oncogene to promote multiple myeloma cell proliferation and antiapoptosis. These encourage the clinical development of FGFR3-specific inhibitors. Three short hairpin RNAs (shRNA) targeting different sites of FGFR3 were selected and subsequently transfected into KMS-11, OPM-2, and NCI-H929 human myeloma cell lines, all of which are characterized by t(4;14) and FGFR3 over expression. The combination of these three shRNAs can effectively inhibit FGFR3 expression in all three cell lines. Sequential immunocytochemistry/fluorescence in situ hybridization was employed to validate that the shRNAs specifically inhibited FGFR3 expression in OPM-2 cells. Decreased expression of B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2) and myeloid cell leukemia sequence 1 (MCL1) proteins and increased staining of Annexin V-positive cells showed that inhibition of FGFR3 induces apoptosis. After confirming down-regulation of FGFR3 by real-time PCR, HU-133 plus 2.0 array was employed to compare the gene expression profile of shRNA-treated sample with that of the control. Besides the down-regulation of FGFR3, expression of the antiapoptotic genes CFLAR, BCL2, MCL1, and some members of NF-kappaB family decreased, whereas expression of the proapoptotic genes CYC, BID, CASP2, and CASP6 increased. Microarray results also revealed changes in genes previously implicated in multiple myeloma pathogenesis (RAS, RAF, IL-6R, and VEGF), as well as others (TLR4, KLF4, and GADD45A) not previously linked to multiple myeloma. Our observations indicate that shRNAs can specifically and effectively inhibit FGFR3 expression. This targeted approach may be worth testing in multiple myeloma patients with t(4;14) and FGFR3 overexpression in the future.
Mol Cancer Ther 2005 May
PMID:Fibroblast growth factor receptor 3 inhibition by short hairpin RNAs leads to apoptosis in multiple myeloma. 1589 43

Cyclooxygenase-2 (COX-2) has been reported to be associated with tumor development and progression as well as to protect cells from apoptosis induced by various cellular stresses. Through a tetracycline-regulated COX-2 overexpression system, we found that COX-2 inhibits detachment-induced apoptosis (anoikis) in a human bladder cancer cell line, EJ. We also found that the inhibition of anoikis by COX-2 results from activation of the PI-3K/Akt pathway as evidenced by suppression of the COX-2 effect on anoikis by a PI-3K inhibitor, LY294002. Furthermore, COX-2 enhanced Mcl-1 expression in the anoikis process, implying that Mcl-1 also may be involved in mediating the survival function of COX-2. Together, these results suggest that COX-2 inhibits anoikis by activation of the PI-3K/Akt pathway and probably by enhancement of Mcl-1 expression in human bladder cancer cells. This anti- anoikis effect of COX-2 may be a part of mechanisms to promote tumor development and progression.
Exp Mol Med 2005 Jun 30
PMID:COX-2 inhibits anoikis by activation of the PI-3K/Akt pathway in human bladder cancer cells. 1600 Aug 74

Poly(ADP-ribose) polymerases or PARPs are a family of NAD(+)-dependent enzymes that modify themselves and other substrate proteins with ADP-ribose polymers. The founding member PARP 1 is localized predominantly in the nucleus and is activated by binding to DNA lesions. Excessive PARP 1 activation following genotoxin treatment causes NAD(+) depletion and cell death, whereas pharmacological PARP 1 inhibition protects cells from genotoxicity. This study investigates whether cellular viability and NAD(+) metabolism are regulated by tankyrase-1, a PARP member localized predominantly in the cytosol. Using a tetracycline-sensitive promoter to regulate tankyrase-1 expression in Madin-Darby canine kidney (MDCK) cells, we found that a 40-fold induction of tankyrase-1 (from 1,500 to 60,000 copies per cell) lowers steady-state NAD(+) levels but does not affect basal cellular viability. Moreover, the induction confers protection against the oxidative agent H(2)O(2) and the alkylating agent MNNG, genotoxins that kill cells by activating PARP 1. The cytoprotective effect of tankyrase-1 is not due to enhanced scavenging of oxidants or altered expression of Mcl-1, an anti-apoptotic molecule previously shown to be down-regulated by tankyrase-1 in CHO cells. Instead, tankyrase-1 appears to protect cells by preventing genotoxins from activating PARP 1-mediated reactions such as PARP 1 automodification and NAD(+) consumption. Our findings therefore indicate a cytoprotective function of tankyrase-1 mediated through altered NAD(+) homeostasis and inhibition of PARP 1 function.
Mol Cell Biochem 2005 Aug
PMID:Tankyrase-1 overexpression reduces genotoxin-induced cell death by inhibiting PARP1. 1613

Determinants of differentiation and apoptosis induction by the novel histone deacetylase inhibitor (HDACI) LAQ824 were examined in human leukemia cells (U937 and Jurkat). Exposure of U937 cells to a low concentration of LAQ824 (30 nM) resulted in a delayed (2 h) increase in reactive oxygen species (ROS), induction of p21(WAF1/CIP1), pRb dephosphorylation, growth arrest of cells in G(0)/G(1) phase, and differentiation. On the other hand, exposure of cells to a higher concentration of LAQ824 (75 nM) resulted in the early (30 min) generation of ROS, arrest of cells in G(2)/M phase, down-regulation of XIAP (at the transcriptional level) and Mcl-1 (through a caspase-mediated process), the acid sphingomyelinase-dependent generation of ceramide, and profound mitochondrial injury, caspase activation, and apoptosis. LAQ824-induced lethality in U937 cells did not involve the extrinsic apoptotic pathway, nor was it associated with death receptor up-regulation; instead, it was markedly inhibited by ectopic expression of Bcl-2, Bcl-x(L), XIAP, and Mcl-1. The free radical scavenger N-acetyl cysteine blocked LAQ824-mediated ROS generation, mitochondrial injury, Mcl-1 down-regulation, ceramide generation, and apoptosis, suggesting a primary role for oxidative injury in LAQ824 lethality. Together, these findings indicate that LAQ824-induced lethality represents a multifactorial process in which LAQ824-mediated ROS generation is necessary but not sufficient to induce apoptosis, and that the degree of XIAP and Mcl-1 down-regulation and ceramide generation determines whether this agent engages a maturation rather than an apoptotic program.
Mol Pharmacol 2006 Jan
PMID:The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury, and the acid sphingomyelinase-dependent generation of ceramide. 3082 54

Interleukin-22 (IL-22) is a recently identified T cell-derived cytokine whose biological significance remains obscure. Previously, we have shown that IL-22 plays a protective role in T cell-mediated hepatitis induced by Concanavalin A (Con A), acting as a survival factor for hepatocytes. In the present paper, we demonstrate that hydrodynamic gene delivery of IL-22 cDNA driven either by a liver-specific albumin promoter or a human cytomegalovirus (CMV) promoter results in IL-22 protein expression, STAT3 activation, and expression of several anti-apoptotic proteins, including Bcl-xL, Bcl-2, and Mcl-1 in the liver. Immunohistochemical analysis reveals that IL-22 protein expression is mainly detected in the cytoplasm of hepatocytes. Overexpression of IL-22 by hydrodynamic gene delivery significantly protects against liver injury, necrosis, and apoptosis induced by administration of Con A, carbon tetrachloride (CCl4), or the Fas agonist Jo-2 mAb. Western blot analyses show that overexpression of IL-22 significantly enhances activation of STAT3 and expression of Bcl-xL, Bcl-2, and Mcl-1 proteins in liver injury induced by Con A. In conclusion, hydrodynamic gene delivery of IL-22 protects against liver injury induced by a variety of toxins, suggesting the therapeutic potential of IL-22 in treating human liver disease.
Cell Mol Immunol 2004 Feb
PMID:Hydrodynamic gene delivery of interleukin-22 protects the mouse liver from concanavalin A-, carbon tetrachloride-, and Fas ligand-induced injury via activation of STAT3. 1621 20

In the present study, we aimed to elucidate the mechanism responsible for the interactive effects of histone deacetylase (HDAC) inhibitors [suberoylanilide hydroxamic acid (SAHA), MS-275, m-carboxycinnamic acid bishydroxamide (CBHA), and trichostatin-A (TSA)] and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on apoptosis in leukemia cells. HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in leukemia cells (HL60, Jurkat, K562, and U937) through multiple mechanisms; up-regulation of DR4, DR5, Bak, Bax, Bim, Noxa and PUMA, down-regulation of IAPs, Mcl-1, Bcl-2, Bcl-XL and cFLIP, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/Htr2) to the cytosol, induction of p21WAF1/CIP1 and p27KIP1, activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). The sequential treatment of cells with HDAC inhibitors followed by TRAIL was more effective in inducing apoptosis than the concurrent treatment or single agent alone. The up-regulation of death receptors and inhibition of cFLIP by HDAC inhibitors will increase the ability of TRAIL to induce apoptosis, due to enhance activation of caspase-8, cleavage of Bid, and release of mitochondrial proteins to the cytosol, and subsequent activation of caspase-9 and caspase-3. Thus, the combination of HDAC inhibitors and TRAIL can be used as a new therapeutic approach for the treatment of leukemia.
Int J Mol Med 2005 Dec
PMID:Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: involvement of both death receptor and mitochondrial pathways. 1627 96

Bcl-2 and Bcl-xL are associated with treatment resistance and progression in many cancers, including prostate cancer. The objective of this study was to determine whether a novel bispecific antisense oligonucleotide targeting both Bcl-2 and Bcl-xL induces apoptosis and enhances chemosensitivity in androgen-independent PC3 prostate cancer cells. An antisense oligonucleotide with complete sequence identity to Bcl-2 and three-base mismatches to Bcl-xL selected from five antisense oligonucleotides targeting various regions with high homology between Bcl-2 and Bcl-xL was found to be the most potent inhibitor of both Bcl-2 and Bcl-xL expression in PC3 cells. This selected Bcl-2/Bcl-xL bispecific antisense oligonucleotide reduced mRNA and protein levels in a dose-dependent manner, reducing Bcl-2 and Bcl-xL protein levels to 12% and 19%, respectively. Interestingly, Mcl-1 was down-regulated as well, although levels of Bax, Bad, or Bak were not altered after treatment with this bispecific antisense oligonucleotide. Indirect down-regulation of inhibitor of apoptosis (IAP) family, including XIAP, cIAP-1 and cIAP-2, via second mitochondria-derived activator of caspases was also observed after bispecific antisense oligonucleotide treatment. Executioner caspase-3, caspase-6, and caspase-7 were shown to be involved in apoptosis induced by bispecific antisense oligonucleotide. This Bcl-2/Bcl-xL bispecific antisense oligonucleotide also enhanced paclitaxel chemosensitivity in PC3 cells, reducing the IC50 of paclitaxel by >90%. These findings illustrate that combined suppression of antiapoptotic Bcl-2 family members using this antisense oligonucleotide could be an attractive strategy for inhibiting cancer progression through alteration of the apoptotic rheostat in androgen-independent prostate cancer.
Mol Cancer Ther 2005 Nov
PMID:A novel antisense oligonucleotide inhibiting several antiapoptotic Bcl-2 family members induces apoptosis and enhances chemosensitivity in androgen-independent human prostate cancer PC3 cells. 1627 90

Interactions between the novel histone deacetylase inhibitor LAQ824 and the cyclin-dependent kinase inhibitor roscovitine were examined in human leukemia cells. Pretreatment (24 hours) with a subtoxic concentration of LAQ824 (30 nmol/L) followed by a minimally toxic concentration of roscovitine (10 micromol/L; 24 hours) resulted in greater than additive effects on apoptosis in U937, Jurkat, and HL-60 human leukemia cells and blasts from three patients with acute myelogenous leukemia. These events were associated with enhanced conformational changes in Bax; mitochondrial release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor; and a marked increase in caspase activation. LAQ824/roscovitine-treated cells displayed caspase-dependent down-regulation of p21(CIP1) and Mcl-1 and a pronounced caspase-independent reduction in X-linked inhibitor of apoptosis (XIAP) expression. The lethality of this regimen was significantly attenuated by ectopic expression of XIAP, a nuclear localization signal-defective p21(CIP1) mutant, Mcl-1, and Bcl-2. Combined exposure to LAQ824 and roscovitine resulted in a significant reduction in XIAP mRNA levels and diminished phosphorylation of the carboxyl-terminal domain of RNA polymerase II. Notably, roscovitine blocked LAQ824-mediated differentiation. Finally, LAQ824 and roscovitine individually and in combination triggered an increase in generation of reactive oxygen species; moreover, coadministration of the free radical scavenger N-acetylcysteine prevented LAQ824/roscovitine-mediated mitochondrial injury and apoptosis. Collectively, these findings suggest that combined treatment of human leukemia cells with LAQ824 and roscovitine disrupts maturation and synergistically induces apoptosis, lending further support for an antileukemic strategy combining novel histone deacetylase and cyclin-dependent kinase inhibitors.
Mol Cancer Ther 2005 Nov
PMID:Potentiation of the lethality of the histone deacetylase inhibitor LAQ824 by the cyclin-dependent kinase inhibitor roscovitine in human leukemia cells. 1627 99

Up-regulated signal transducers and activators of transcription (STAT)-mediated signaling is believed to contribute to the pathogenesis of a variety of solid and hematologic cancers. Consequently, inhibition of STAT-mediated signaling has recently been proposed as a potential new therapeutic approach to the treatment of cancers. Having shown previously that the pan-cyclin-dependent kinase inhibitor flavopiridol binds to DNA and seems to kill cancer cells via that process in some circumstances, we evaluated the hypothesis that flavopiridol might consequently disrupt STAT3/DNA interactions, attenuate STAT3-directed transcription, and down-regulate STAT3 downstream polypeptides, including the antiapoptotic polypeptide Mcl-1. SDS-PAGE/immunoblotting and reverse transcription-PCR were used to assess RNA and polypeptide levels, respectively. DNA cellulose affinity chromatography and a nuclear elution assay were used to evaluate the ability of flavopiridol to disrupt STAT3/DNA interactions. A STAT3 luciferase reporter assay was used to examine the ability of flavopiridol to attenuate STAT3-directed transcription. Colony-forming assays were used to assess cytotoxic synergy between flavopiridol and AG490. Flavopiridol was found to (a) disrupt STAT3/DNA interactions (DNA cellulose affinity chromatography and nuclear elution assay), (b) attenuate STAT3-directed transcription (STAT3 luciferase reporter assay), and (c) down-regulate the STAT3 downstream antiapoptotic polypeptide Mcl-1 at the transcriptional level (reverse transcription-PCR and SDS-PAGE/immunoblotting). Furthermore, flavopiridol, but not the microtubule inhibitor paclitaxel, could be combined with the STAT3 pathway inhibitor AG490 to achieve cytotoxic synergy in A549 human non-small cell lung cancer cells. Collectively, these data suggest that flavopiridol can attenuate STAT3-directed transcription in a targeted fashion and may therefore be exploitable clinically in the development of chemotherapy regimens combining flavopiridol and other inhibitors of STAT3 signaling pathways.
Mol Cancer Ther 2006 Jan
PMID:Flavopiridol disrupts STAT3/DNA interactions, attenuates STAT3-directed transcription, and combines with the Jak kinase inhibitor AG490 to achieve cytotoxic synergy. 1643 72

Multiple myeloma is an incurable disease for the majority of patients, therefore requiring new biological targeted therapies. In primary myeloma cells, IMP dehydrogenase (IMPDH) was shown to be consistently overexpressed. We therefore tested the IMPDH inhibitor mycophenolate mofetil (MMF) currently available as a clinical therapeutic agent for its antimyeloma activity in vitro. MMF depleted intracellular guanosine 5'-triphosphate (GTP) levels in myeloma cells. We showed apoptosis induction in myeloma cell lines and primary myeloma cells between 1 and 5 mumol/L MMF. MMF was also cytotoxic at this concentration in dexamethasone-resistant and Mcl-1-overexpressed myeloma cell lines shown by the tetrazolium salt XTT assay along with cell survival measured by a modified flow cytometric assay. Apoptosis was not inhibited by the presence of an antioxidant, suggesting that MMF-induced apoptosis is less likely to be associated with reactive oxygen species. However, apoptosis was abrogated by exogenously added guanosine, which activates an alternative pathway for GTP formation, implicating that this effect is directly mediated by IMPDH inhibition. MMF-induced G1-S phase cell cycle arrest and its apoptosis induction mechanism were associated with a caspase-dependent pathway as shown by alteration of mitochondrial membrane potential and cytochrome c release followed by activation of the caspases. MMF-induced apoptosis was also inhibited by a pan-caspase inhibitor Z-VAD-fmk. MMF-treated myeloma cells showed an up-regulation of Bak, which most likely together with Bax resulted in the release of cytochrome c. In summary, MMF attenuates G1-S phase cell cycle progression and activates the pathway of mitochondrial dysfunction, leading to cytochrome c release followed by activation of caspases.
Mol Cancer Ther 2006 Feb
PMID:IMP dehydrogenase inhibitor mycophenolate mofetil induces caspase-dependent apoptosis and cell cycle inhibition in multiple myeloma cells. 1650 21


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