Apoptosis Induction by a Novel Retinoid-Related Molecule Requires Nuclear Factor-κB Activation

John D Dingell Veterans Affairs Medical Center, Detroit, Michigan 48201, USA.
Cancer Research (Impact Factor: 9.33). 07/2005; 65(11):4909-17. DOI: 10.1158/0008-5472.CAN-04-4124
Source: PubMed


Nuclear factor-kappaB (NF-kappaB) activation has been shown to be both antiapoptotic and proapoptotic depending on the stimulus and the specific cell type involved. NF-kappaB activation has also been shown to be essential for apoptosis induction by a number of agents. The novel retinoid-related molecule 4-[3-Cl-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) activates NF-kappaB with subsequent apoptosis in a number of cell types. We have found that NF-kappaB activation is essential for 3-Cl-AHPC-mediated apoptosis. 3-Cl-AHPC activates NF-kappaB through IKKalpha kinase activation and the subsequent degradation of IkappaB alpha. IKKalpha kinase activation is associated with IKKalpha-enhanced binding to HSP90. The HSP90 inhibitor geldanamycin enhances the degradation of IKKalpha and blocks 3-Cl-AHPC activation of NF-kappaB and 3-Cl-AHPC-mediated apoptosis. In addition, inhibition of IkappaB alpha degradation using a dominant-negative IkappaB alpha inhibits 3-Cl-AHPC-mediated apoptosis. NF-kappaB p65 activation is essential for 3-Cl-AHPC apoptosis induction as evidenced by the fact that inhibition of p65 activation utilizing the inhibitor helenalin or loss of p65 expression block 3-Cl-AHPC-mediated apoptosis. NF-kappaB has been shown to be antiapoptotic through its enhanced expression of a number of antiapoptotic proteins including X-linked inhibitor of apoptosis protein (XIAP), c-IAP1, and Bcl-X(L). Whereas exposure to 3-Cl-AHPC results in NF-kappaB activation, it inhibits the expression of XIAP, c-IAP1, and Bcl-X(L) and enhances the expression of proapoptotic molecules, including the death receptors DR4 and DR5 as well as Fas and Rip1. Thus, 3-Cl-AHPC, which is under preclinical development, has pleotrophic effects on malignant cells resulting in their apoptosis.


Available from: Lulu Farhana, Jul 02, 2014
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    • "Furthermore, activation of NF-κB by UV light and doxorubicin converts it into an active repressor of the anti-apoptotic genes XIAP and Bcl-xL [8]. Additional evidence supporting a pro-apoptotic role for NF-κB in cancer chemotherapy comes from the observation that the retinoid-related compounds 3-Cl-AHPC and CD437 require activation of NF-κB in order to induce apoptosis in DU145 and PC3 castration-resistant prostate cancer (CRPC) cells [9,10]. Exposure of CRPC cells to 3-Cl-AHPC or CD437 enhances the expression of the pro-apoptotic Death Receptor (DR) 4 and 5 genes. "
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    ABSTRACT: NF-kappaB is a transcription factor that promotes inhibition of apoptosis and resistance to chemotherapy. It is commonly believed that inhibition of NF-kappaB activity can increase sensitivity of cancer cells to chemotherapy. However, there is evidence that NF-kappaB activation can sensitize cells to apoptosis and that inhibition of NF-kappaB results in resistance to chemotherapy. In prostate cancer, it is not clear in the different cell types (androgen-dependent and castration-resistant) if activation or inhibition of NF-kappaB is required for stimulation of apoptosis by chemotherapy. Our data indicate that the response of prostate cancer (PC) cells to the antimitotic drugs docetaxel (Doc) and 2-methoxyestradiol (2ME2) is dependent on the levels of NF-kappaB activity. In androgen-dependent LNCaP cells, Doc and 2ME2 treatment increased the low basal NF-kappaB activity, as determined by Western blot analysis of phospho-IkappaBalpha/p65, NF-kappaB promoter reporter assays, and p65 localization. Treatment of LNCaP cells with parthenolide, a pharmacologic inhibitor of NF-kappaB, or introduction of dominant-negative IkappaBalpha, or an shRNA specific for p65, a component of the NF-kappaB heterodimer, blocked apoptosis induced by Doc and 2ME2. In castration-resistant DU145 and PC3 cells, Doc and 2ME2 had little effect on the high basal NF-kappaB activity and addition of parthenolide did not enhance cell death. However, the combination of Doc or 2ME2 with betulinic acid (BA), a triterpenoid that activates NF-kappaB, stimulated apoptosis in LNCaP and non-apoptotic cell death in DU145 and PC3 cells. Increased sensitivity to cell death mediated by the Doc or 2ME2 + BA combination is likely due to increased NF-kappaB activity. Our data suggest that the combination of antimitotic drugs with NF-kappaB inhibitors will have antagonistic effects in a common type of PC cell typical of LNCaP. However, combination strategies utilizing antimitotic drugs with BA, an activator of NF-kappaB, will universally enhance cell death in PC cells, notably in the aggressive, castration-resistant variety that does not respond to conventional therapies.
    Molecular Cancer 07/2010; 9(1):182. DOI:10.1186/1476-4598-9-182 · 4.26 Impact Factor
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    • "which down-regulates the inflammatory response and promotes cell survival. However, in concordance with our data, Farhana et al. (2005) showed that the pro-apoptotic effect of NFkB activation after stimulation by retinoid-related molecule (3-Cl-AHPC) is through inhibition of antiapoptotic proteins c-IAP-1, XIAP and Bcl-X L and enhanced expression of pro-apoptotic molecules in a number of cell types. Thus, it appears that NFkB activation is likely to be both anti-apoptotic and pro-apoptotic, depending on the stimulus and the specific cell type involved. "
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    ABSTRACT: The interaction between epithelial cells and micro-organisms is often a crucial initiating event in infectious diseases. Infection with Porphyromonas gingivalis, a Gram-negative anaerobe, is strongly associated with severe periodontal disease. This bacterium possesses an array of virulence factors, some of which can induce apoptosis. The tumour necrosis factor (TNF) receptor family is involved in the regulation of cellular homeostasis, cell surface molecules involved in phagocytosis, Fas ligand (L) expression and activation of the caspase cascade resulting in DNA fragmentation and cell blebbing. The current study examined the role of nuclear factor-kappaB (NFkappaB) in FasL-mediated apoptotic cell death in primary human gingival epithelial cells (HGEC) induced by heat-killed P. gingivalis, probably through TLR signalling pathways. A marked up-regulation of TLR2 and Fas-FasL was detected in HGEC stimulated with P. gingivalis. Activation of NFkappaB by P. gingivalis in HGEC was demonstrated by an NFkappaB promoter luciferase assay as well as by phosphorylation of p65 as detected by Western blotting. Activation of cleaved caspase-3 and caspase-8 resulted in apoptotic cell death of HGEC. The survival proteins c-IAP-1/c-IAP-2 were decreased in HGEC exposed to P. gingivalis. HGEC apoptosis induced by P. gingivalis was inhibited by an anti-human FasL monoclonal antibody. Blockade of NFkappaB by helenalin resulted in down-regulation of FasL whereas a caspase-8 inhibitor did not decrease FasL. Taken together, these studies show that P. gingivalis can induce epithelial cell apoptosis through Fas-FasL up-regulation and activation of caspase-3 and caspase-8.
    Microbiology 04/2006; 152(Pt 3):797-806. DOI:10.1099/mic.0.28472-0 · 2.56 Impact Factor
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    • "CCI-779 (a rapamycin analogue) was shown to sensitize multiple myeloma cells to dexamethasone-induced apoptosis by decreasing cap-dependent translation of a number of apoptotic regulators including c-IAP1 and XIAP (Yan et al. 2006). Finally, drugs that antagonize PI3K/Akt or NF-κB signaling, with subsequent decreases in c-IAP1 protein levels, have also been shown to enhance sensitivity to chemotherapeutics (Liu et al. 2006;Farhana et al. 2005;Machuca et al. 2006). In sum, these studies suggest that c-IAP1 may have a causal role in promoting an aggressive, drug-resistant phenotype. "
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    ABSTRACT: [School of Medicine] Department of Pharmacology Thesis (Ph. D.)--Case Western Reserve University, 2007. Includes bibliographical references. Requires Adobe Acrobat Reader for viewing.
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