Implication of multiple mechanisms in apoptosis induced by the synthetic retinoid CD437 in human prostate carcinoma cells

Sun, Shi-Yong; Yue, Ping; Lotan, Reuben

doi:10.1038/sj.onc.1203810

Cited by 61 publications

(58 citation statements)

References 49 publications

(63 reference statements)

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“…This finding is in line with the observations from other laboratories, which demonstrated that these compounds can induce apoptosis in various cancerous cell lines via RAR + -independent pathways [30]. Several mechanisms have been demonstrated to participate in this, including upregulation of p53 [31], c-myc [32], AP-1 [33], various cell death receptors [34] or CRAP-1 [35], but the exact target of CD437 or CD2325 has not been identified yet. Our data are the first to show that, in T cells, CD437 and the structurally related CD2325 can induce apoptosis via a pathway that involves both RAR + -independent and -dependent elements including up-regulation of nur77 and cell surface FasL, and sensitization of the Fas death receptor mediated pathway.…”

Section: Discussionsupporting

confidence: 87%

Retinoids induce Fas(CD95) ligand cell surface expression via RARγ and nur77 in T cells

et al. 2004

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Cells from the CD4 + murine T hybridoma line IP-12-7 enter the apoptotic suicide program via the Fas ligand (FasL)/Fas-mediated pathway upon TCR stimulation. This stimulus regulates the sensitization of the Fas death pathway and the cell surface appearance of preformed FasL. The apoptosis is dependent on new mRNA and protein synthesis and involves upregulation of nur77. Two groups of nuclear receptors for retinoic acids (RA) have been identified: retinoic acid receptors (RAR) and retinoid X receptors. IP-12-7 cells express RAR § and RAR + . Here we show that, in the IP-12-7 T cells, RA also induced the expression and DNA binding of nur77, and the cell surface appearance of FasL. The induction was mediated via RAR + . Despite the induced expression of cell surface FasL, only two structurally related RAR + -selective compounds, CD437 and CD2325, initiated apoptosis in these cells. The lack of apoptosis induction by natural RA was related to the inability of RAR + to sensitize the Fas death-pathway. Cell surface FasL, however, was able to induce cell death in Fas-bearing target cells. Natural RA also induced the expression of FasL in phytohemagglutinin-activated peripheral murine T cells. It is proposed that therapeutically administered RA might induce apoptosis in Fas-sensitive cells via induction of FasL expression in activated T cells.

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Section: Discussionsupporting

confidence: 87%

Retinoids induce Fas(CD95) ligand cell surface expression via RARγ and nur77 in T cells

et al. 2004

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“…[38][39][40] Apoptosis-inducing compounds, such as quercetin, 38 mercury chloride, 39 and vitamin K 3 , 40 cause an increase in c-Fos mRNA within 15-60 min that returns to basal levels within 2 h. Interestingly, c-Fos upregulation by treatment with the retinoid CD437 could be detected only after prolonged treatment of melanoma cells with the drug, that is at 24 and 48 h. 35 Also in prostate cancer cells, CD437 treatment caused a sustained c-Fos upregulation for 32 h even though it could already be detected after 4 h of treatment. 37 Overall, such results indicate that enhanced and prolonged expression of c-Fos may be a relevant event for retinoidinduced apoptosis in a variety of cell types. However, the mechanisms through which retinoids enhance c-Fos expression levels have not been elucidated.…”

Section: Discussionmentioning

confidence: 85%

“…In fact, the synthetic retinoid CD437 (6-(-2-naphthalene carboxylic acid), a potent inducer of apoptosis, was shown to upregulate c-Fos expression in tumor cells of different types such as melanoma, 35 head and neck, 36 and prostate cancer. 37 In HPR-treated A2780 cells, c-Fos mRNA level was not modified at 6 h, but it was upregulated within 24 h and it continued to increase for a prolonged period of time (48 h). The c-Fos expression profile that we described here, that is a late and sustained induction, is different from the cFos induction profiles described with other apoptotic-inducing agents as rapid and transient.…”

Section: Discussionmentioning

confidence: 89%

Involvement of c-Fos in fenretinide-induced apoptosis in human ovarian carcinoma cells

et al. 2003

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Fenretinide (HPR), a synthetic retinoid that exhibits lower toxicity than other retinoids, has shown preventive and therapeutic activity against ovarian tumors. Although the growth inhibitory effects of HPR have been ascribed to its ability to induce apoptosis, little is known about the molecular mechanisms involved. Since the proto-oncogene c-Fos has been implicated in apoptosis induction, we analyzed its role in mediating HPR response in a human ovarian carcinoma cell line (A2780) sensitive to HPR apoptotic effect. In these cells, HPR treatment caused induction of c-Fos expression, whereas such an effect was not observed in cells made resistant to HPR-induced apoptosis (A2780/HPR). Moreover, in a panel of other human ovarian carcinoma cell lines, c-Fos inducibility and HPR sensitivity were closely associated. Ceramide, which is involved in HPR-induced apoptosis, was also involved in cFos induction because its upregulation by HPR was reduced by fumonisin B 1 , a ceramide synthase inhibitor. The causal relationship between c-Fos induction and apoptosis was established by the finding of an increased apoptotic rate in cells overexpressing c-Fos. Similarly to that observed for c-Fos expression, HPR treatment increased c-Jun expression in HPR-sensitive but not in HPR-resistant cells, suggesting the involvement of the transcription factor activating protein 1 (AP-1) in HPR-induced apoptosis. In gene reporter experiments, HPR stimulated AP-1 transcriptional activity and potentiated the AP-1 activity induced by 12-tetradecanoylphorbol 13-acetate. Furthermore, inhibition of AP-1 DNA binding, by transfecting A2780 cells with a dominantnegative Fos gene, caused decreased sensitivity to HPR apoptotic effects. Overall, the results indicate that c-Fos plays a role in mediating HPR-induced growth inhibition and apoptosis in ovarian cancer cells and suggest that c-Fos regulates these processes as a member of the AP-1 transcription factor.

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“…6,7,11,[39][40][41] Recently, it has been shown that another retinoid, CD437, enhances TRAIL-mediated apoptosis in prostate and lung cancer cells. 57,58 The increase in TRAIL-mediated apoptosis induced by the retinoid CD437 has been explained by upregulation of TRAIL-R1 and TRAIL-R2 in lung cancer cells in a p53-dependent manner. 57 However, in prostate cancer cells, there is no clear correlation between upregulation of the death receptors and the increase in TRAIL-mediated toxicity induced by CD437.…”

Section: Discussionmentioning

confidence: 99%

“…57 However, in prostate cancer cells, there is no clear correlation between upregulation of the death receptors and the increase in TRAIL-mediated toxicity induced by CD437. 58 Using 4HPR, we investigated multiple proteins known to modulate TRAIL sensitivity. No changes were detected in the expression of any of them, including TRAIL death receptors, FLIPs, IAPs, survivin, and different kinases involved in cell proliferation and survival (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines

et al. 2004

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The majority of ovarian cancer cells are resistant to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Subtoxic concentrations of the semisynthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) enhanced TRAIL-mediated apoptosis in ovarian cancer cell lines but not in immortalized nontumorigenic ovarian epithelial cells. The enhancement of TRAIL-mediated apoptosis by 4HPR was not due to changes in the levels of proteins known to modulate TRAIL sensitivity. The combination of 4HPR and TRAIL enhanced cleavage of multiple caspases in the death receptor pathway (including the two initiator caspases, caspase-8 and caspase-9). The 4HPR and TRAIL combination leads to mitochondrial permeability transition, significant increase in cytochrome c release, and increased caspase-9 activation. Caspase-9 may further activate caspase-8, generating an amplification loop. Stable overexpression of Bcl-xL abrogates the interaction between 4HPR and TRAIL at the mitochondrial level by blocking cytochrome c release. As a consequence, a decrease in activation of caspase-9, caspase-8, and TRAIL-mediated apoptosis occurs. These results indicate that the enhancement in TRAIL-mediated apoptosis induced by 4HPR is due to the increase in activation of multiple caspases involving an amplification loop via the mitochondrial-death pathway. These findings offer a promising and novel strategy for the treatment of ovarian cancer.

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Implication of multiple mechanisms in apoptosis induced by the synthetic retinoid CD437 in human prostate carcinoma cells

Cited by 61 publications

References 49 publications

Retinoids induce Fas(CD95) ligand cell surface expression via RARγ and nur77 in T cells

Retinoids induce Fas(CD95) ligand cell surface expression via RARγ and nur77 in T cells

Involvement of c-Fos in fenretinide-induced apoptosis in human ovarian carcinoma cells

N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines

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