Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

Holmes, William F.; Soprano, Dianne Robert; Soprano, Kenneth J.

doi:10.1002/jcp.10338

Cited by 42 publications

(39 citation statements)

References 150 publications

(155 reference statements)

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“…AHPN/ CD437, currently being evaluated in clinical trials as anticancer agent, causes growth arrest and apoptosis in p53 and Nur77/TR3 UM Moll et al epithelial cancer models in vitro and in vivo (Costantini et al, 2000;Fontana and Rishi, 2002;Zhang, 2002;Lotan, 2003;Pfahl and Piedrafita, 2003;Holmes et al, 2004). Although highly complex in its pro-apoptotic actions, in CA-OVOC3 ovarian cancer cells AHPN/ CD437 kills through a signaling pathway independent of retinoid receptor activation.…”

Section: Nur77 As a Death Factormentioning

confidence: 99%

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

2006

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The complex apoptotic functions of the p53 tumor suppressor are central to its antineoplastic activity in vivo. Conversely, p53 function is altered or attenuated in one way or another in the majority of human cancers. Besides its well-understood action as a transcriptional regulator of multiple apoptotic genes, p53 also exerts a direct pro-apoptotic role at the mitochondria by engaging in protein-protein interactions with anti-and pro-apoptotic Bcl2 family members, thereby executing the shortest known circuitry of p53 death signaling. Nur77, also known as TR3 or NGFI-B, is a unique transcription factor belonging to the orphan nuclear receptor superfamily. Even more extreme than p53, Nur77 can exert opposing biological activities of survival and death. Its activities are regulated by subcellular distribution, expression levels, protein modification and heterodimerization with retinoid X receptor. In cancer cells, Nur77 functions in the nucleus as an oncogenic survival factor, but becomes a potent killer when certain death stimuli induce its migration to mitochondria, where it binds to Bcl2 and conformationally converts it to a killer that triggers cytochrome c release and apoptosis. This review focuses on their unexpected transcription-independent pro-death programs at mitochondria and highlights the remarkable mechanistic similarities between them. Moreover, an accumulating body of evidence provides ample rationale to further investigate how these mitochondrial p53 and Nur77 pathways could become exploitable targets for new cancer therapeutics.

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Section: Nur77 As a Death Factormentioning

confidence: 99%

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

2006

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“…One of these activities is the induction of apoptosis (Sheikh et al, 1995;Fanjul et al, 1996;Wu et al, 1998a;Holmes et al, 2000Holmes et al, , 2002Holmes et al, , 2003aHolmes et al, 2004). Synthetic retinoids are defined as man-made compounds that are structurally and functionally similar to natural retinoids (Dawson and Hobbs, 1994).…”

Section: T986mentioning

confidence: 99%

Rb2/p130 and protein phosphatase 2A: key mediators of ovarian carcinoma cell growth suppression by all-trans retinoic acid

et al. 2006

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Despite a number of attempts to improve treatment of ovarian cancer, it remains the most common cause of death from gynecological cancers. Thus, it is very important to identify more effective drugs for treatment and prevention of ovarian cancer. All-trans-retinoic acid (ATRA) has been shown to arrest the growth of ovarian carcinoma cells in G0/G1 and to significantly elevate levels of Rb2/p130 protein, a member of the retinoblastoma family of tumor suppressors. As ATRA treatment leads to a significant increase in the amount of Rb2/p130 protein but not mRNA, the elevated levels of Rb2/p130 protein is likely the result of increased stability. In studies to elucidate the mechanism by which ATRA alters Rb2/ p130 stability in ovarian cancer cells, it was determined that PP2A, a serine/threonine phosphatase, binds and dephosphorylates Rb2/p130. Dephosphorylated Rb2/p130 exhibits decreased ubiquitination and thus is not degraded by the proteasome. The sites at which PP2A catalytic subunit (PP2Ac) interacts with Rb2/p130 have been localized to the NLS in the C-terminus of Rb2/p130. These sites are also involved in the interaction of Rb/p130 with importin b and importin a, members of the nuclear transport machinery. It is known that importin a recognizes a NLS on a target protein and importin b binds the nuclear pore complex. Moreover, it has been shown that the binding of importin a to NLS significantly decreases with phosphorylation of NLS. In ATRA-treated ovarian carcinoma cells, PP2A binds to Rb2/p130 and dephosphorylates the NLS of Rb2/p130 leading to the interaction of importin a with Rb2/p130. Importin b then binds to the importin a-Rb2/p130 complex, leading to the translocation of the Rb2/p130 to the nucleus where it acts to arrest ovarian cancer cells in G1 and suppress proliferation.

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“…Diet-derived bioactive agents such as indole-3-carbinol, diindolylmethane, retinoic acid, and sulforaphane (4 -6) have been identified as having anticancer properties against different cancer types. However, there are only a few reports on the use of dietary components as chemopreventive agents for ovarian cancer (4,7), although there are many reports with other cancers (5,8). Cruciferous vegetables, particularly broccoli (9), have a high content of glucosinolates, and their hydrolysis results in the generation of metabolites responsible for the anticarcinogenic activity.…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells

Chaudhuri

Oršulić

Ashok

2007

Molecular Cancer Therapeutics

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Epidemiologic studies show a correlation between increased consumption of fruits and vegetables with reduced risk of ovarian cancer. One major bioactive compound found in cruciferous vegetables, particularly broccoli, is sulforaphane, derived from the breakdown of glucoraphanin. We observed potent antiproliferative effects of sulforaphane on human ovarian cancer cell line SKOV3 (IC 50 40 Mmol/L) and mouse ovarian cancer cell lines C3 and T3 (IC 50 25 Mmol/L each) by cell viability assays. The loss of viability is reflected by a downregulation of cell cycle transition regulators cyclin D1, cyclin-dependent kinase 4 (cdk4), and cdk6. The upstream mediators of sulforaphane effects on the cell cycle in ovarian cancer are still unknown. However, because the Akt signal transduction pathway is overactivated in ovarian cancer, we investigated the effects of sulforaphane on this prosurvival pathway. Both total Akt protein and active phosphorylated levels of Akt (Ser 473 ) and phosphoinositide 3-kinase were significantly decreased in sulforaphane-treated SKOV3, C3, and T3 cells with a concomitant inhibition of Akt kinase activity by sulforaphane in SKOV3 and C3 cells. This inhibitory effect of sulforaphane leads to a potent induction of apoptosis in all three cell lines, along with the cleavage of poly(ADP)-ribose polymerase. Our study is the first to report the antiproliferative effects of sulforaphane in ovarian cancer and identifying the Akt pathway as a target of sulforaphane, with implications for the inhibition of carcinogenesis by diet-based chemoprevention. [Mol Cancer Ther 2007;6(1):334 -45]

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Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

Cited by 42 publications

References 150 publications

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction

Rb2/p130 and protein phosphatase 2A: key mediators of ovarian carcinoma cell growth suppression by all-trans retinoic acid

Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells

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