Effects of IKK inhibitor PS1145 on NF-κB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells

Yemelyanov, Alexander; Gasparian, Alexander V.; Lindholm, Paul F.; Dang, Lenny; Pierce, J W; Kisseljov, F. L.; Карселадзе, А. И.; Budunova, Irina

doi:10.1038/sj.onc.1209066

Cited by 108 publications

(91 citation statements)

References 56 publications

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“…With longer exposure, however, both agents reduced cell number and stimulated apoptosis. These observations support the results of previous studies that have shown that IKK plays a key role in the regulation of cancer cell migration and the development of metastases (6,17,37). The greater potency of celastrol coupled with the fact that it inhibited expression of several genes that promote the development of metastases including PTHrP, MMP9, and uPAR suggests that signaling pathways downstream of TAK1 and/or independent of IKK activation may be responsible for the effects that we observed.…”

Section: Discussionsupporting

confidence: 81%

“…Over recent years, interest has focused on the role of IKK as a therapeutic target for the treatment of tumor cell growth and osteoclastic bone resorption. Genetic inactivation of IKKβ inhibits osteoclastogenesis (11) and other studies have shown that pharmacologic and genetic inactivation of IKKα and IKKβ inhibit proliferation of cancer cells in vitro and prevent development of distant metastases in vivo (16,17,37). Taken together, these data suggest that IKK inhibitors might be particularly valuable in the treatment of cancers that metastasize to bone, but the effects of pharmacologic inhibitors of IKK on osteolytic bone loss are unknown.…”

Section: Discussionmentioning

confidence: 66%

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Pharmacologic inhibitors of IκB kinase suppress growth and migration of mammary carcinosarcoma cellsin vitroand prevent osteolytic bone metastasisin vivo

Idris

Libouban

Nyangoga

et al. 2009

Molecular Cancer Therapeutics

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The NF-κB signaling pathway is known to play an important role in the regulation of osteoclastic bone resorption and cancer cell growth. Previous studies have shown that genetic inactivation of IκB kinase (IKK), a key component of NF-κB signaling, inhibits osteoclastogenesis, but the effects of pharmacologic IKK inhibitors on osteolytic bone metastasis are unknown. Here, we studied the effects of the IKK inhibitors celastrol, BMS-345541, parthenolide, and wedelolactone on the proliferation and migration of W256 cells in vitro and osteolytic bone destruction in vivo. All compounds tested inhibited the growth and induced apoptosis of W256 cells as evidenced by caspase-3 activation and nuclear morphology. Celastrol, BMS-345541, and parthenolide abolished IL1β and tumor necrosis factor α-induced IκB phosphorylation and prevented nuclear translocation of NF-κB and DNA binding. Celastrol and parthenolide but not BMS-345541 prevented the activation of both IKKα and IKKβ, and celastrol inhibited IKKα/β activation by preventing the phosphorylation of TAK1, a key receptor-associated factor upstream of IKK. Celastrol and parthenolide markedly reduced the mRNA expression of matrix metalloproteinase 9 and urinary plasminogen activator, and inhibited W256 migration. Administration of celastrol or parthenolide at a dose of 1 mg/kg/day suppressed trabecular bone loss and reduced the number and size of osteolytic bone lesions following W256 injection in rats. Histomorphometric analysis showed that both compounds decreased osteoclast number and inhibited bone resorption. In conclusion, pharmacologic inhibitors of IKK are effective in preventing osteolytic bone metastasis in this model and might represent a promising class of agents to the prevention and treatment of metastatic bone disease associated with breast cancer.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 66%

Pharmacologic inhibitors of IκB kinase suppress growth and migration of mammary carcinosarcoma cellsin vitroand prevent osteolytic bone metastasisin vivo

Idris

Libouban

Nyangoga

et al. 2009

Molecular Cancer Therapeutics

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“…Using real-time PCR, we observed a 20-30% suppression of HB-EGF induction in response to PS1145/SN38 treatments compared to SN38 treatment alone as shown in Figure 2a. Because PS1145 is a potent inhibitor of NF-kB activity (Yemelyanov et al, 2006), these data suggest that HB-EGF induction by SN38 treatment may be regulated by NF-kB.…”

Section: Hb-egf Expression Is Elevated In Response To Chemotherapy Trmentioning

confidence: 80%

Heparin-binding EGF-like growth factor is an early response gene to chemotherapy and contributes to chemotherapy resistance

et al. 2006

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We have shown that one of the principle mechanisms of chemotherapy resistance involves the activation of nuclear factor kappa-B (NF-jB). In an effort to identify NF-jBregulated chemotherapy response genes, we performed a microarray assay and observed that heparin-binding EGFlike growth factor (HB-EGF) was significantly upregulated by SN38 (a strong inducer of NF-jB activity) in colon cancer cells. Further studies revealed that HB-EGF was rapidly induced following a variety of chemotherapy treatments. Using RNA interference, we demonstrated that the chemotherapy-induced HB-EGF was largely dependent on activator protein-1 (AP-1) and NF-jB activation. Constitutive HB-EGF expression rescued AP-1/NF-jB small interfering RNA (siRNA) cells from chemotherapyinduced apoptosis. Meanwhile, we found that the enzymatic shedding of HB-EGF was also regulated by chemotherapy treatment, resulting in the elevated release of soluble HB-EGF from the cellular membrane. Induction of HB-EGF expression and ectodomain shedding synergistically led to robust epidermal growth factor receptor (EGFR) phosphorylation, whereas inhibition of HB-EGF expression by use of the HB-EGF inhibitor (CRM197) or siRNA resulted in the suppression of chemotherapyinduced EGFR phosphorylation. These results suggest that the chemotherapy-induced EGFR activation is regulated by HB-EGF. Finally, we demonstrated that overexpression of HB-EGF led to apoptotic resistance to chemotherapy, whereas suppression of HB-EGF expression by siRNA resulted in a dramatic increase in cell death. In summary, our study suggests that chemotherapy-induced HB-EGF activation represents a critical mechanism of inducible chemotherapy resistance. Therefore, therapeutic intervention aimed at inhibiting HB-EGF activity may be useful in cancer prevention and treatments.

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“…Despite the growing body of literature showing that IKK-beta exerts crucial function in inflammation, immunity, and cancer, the role of IKK-beta in human prostate cancer cells remains largely elusive. Recent evidence using small molecule inhibitors of IKK such as BMS-345541, MLX 105, or PS1145 suggests IKK activity as a potential target for therapy in various malignancies (Lam et al 2005;Yang et al 2006;Yemelyanov et al 2006;Idris et al 2009;Jinawath et al 2010). Our analysis now provides evidence that IKK-beta activity is important for maintaining the integrity of prostate cancer cells.…”

Section: Discovery Of Non-ets Gene Fusions In Prostate Cancermentioning

confidence: 99%

Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing

Pflueger

Terry²,

Sboner³

et al. 2010

Genome Res.

184

156

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Half of prostate cancers harbor gene fusions between TMPRSS2 and members of the ETS transcription factor family. To date, little is known about the presence of non-ETS fusion events in prostate cancer. We used next-generation transcriptome sequencing (RNA-seq) in order to explore the whole transcriptome of 25 human prostate cancer samples for the presence of chimeric fusion transcripts. We generated more than 1 billion sequence reads and used a novel computational approach (FusionSeq) in order to identify novel gene fusion candidates with high confidence. In total, we discovered and characterized seven new cancer-specific gene fusions, two involving the ETS genes ETV1 and ERG, and four involving non-ETS genes such as CDKN1A (p21), CD9, and IKBKB (IKK-beta), genes known to exhibit key biological roles in cellular homeostasis or assumed to be critical in tumorigenesis of other tumor entities, as well as the oncogene PIGU and the tumor suppressor gene RSRC2. The novel gene fusions are found to be of low frequency, but, interestingly, the non-ETS fusions were all present in prostate cancer harboring the TMPRSS2-ERG gene fusion. Future work will focus on determining if the ETS rearrangements in prostate cancer are associated or directly predispose to a rearrangement-prone phenotype.

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Effects of IKK inhibitor PS1145 on NF-κB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells

Cited by 108 publications

References 56 publications

Pharmacologic inhibitors of IκB kinase suppress growth and migration of mammary carcinosarcoma cellsin vitroand prevent osteolytic bone metastasisin vivo

Pharmacologic inhibitors of IκB kinase suppress growth and migration of mammary carcinosarcoma cellsin vitroand prevent osteolytic bone metastasisin vivo

Heparin-binding EGF-like growth factor is an early response gene to chemotherapy and contributes to chemotherapy resistance

Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing

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