Analysis of gene expression identifies PLAB as a mediator of the apoptotic activity of fenretinide in human ovarian cancer cells

Appierto, Valentina; Villani, Maria Grazia; Cavadini, Elena; Gariboldi, Manuela; Cecco, Loris De; Lambert, James R.; Reid, James F.; Tiberio, Paola; Colombo, Nicoletta; Formelli, Franca

doi:10.1038/sj.onc.1210171

Cited by 14 publications

(19 citation statements)

References 34 publications

(37 reference statements)

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“…Western blot analysis showed that 5 µM 4-oxo-4-HPR treatment for 24 hours induced PLAB upregulation and that this effect was strongly reduced by the addition of vitamin C (Figure 3A). To investigate whether PLAB upregulation played a functional role in the apoptosis induced by 4-oxo-4-HPR, we took advantage of PLAB silencing in A2780 cells, previously generated by stable transfection [10]. As expected, PLAB upmodulation induced by 4-oxo-4-HPR was strongly reduced in cells transfected with the PLAB siRNA plasmid compared with cells transfected with a scrambled plasmid used as control (Figure 3B).…”

Section: Resultsmentioning

confidence: 60%

“…We have previously reported that PLAB is upregulated by 4-HPR in a ROS dependent manner [9], and that it plays a functional role in apoptosis induced by the retinoid in A2780 cells [10]. We thus evaluated whether also 4-oxo-4-HPR modulated PLAB expression.…”

Section: Resultsmentioning

confidence: 98%

“…In cultured cells, 4-HPR has been shown to induce growth inhibition and apoptosis in various cancer cell lines and different mechanisms of action have been proposed, including the generation of reactive oxygen species (ROS) and consequent oxidative stress [8], [9]. We have recently reported that in ovarian cancer cells, 4-HPR-induced apoptosis is mediated by the proapoptotic PLAcental Bone morphogenetic protein (PLAB) and that its upregulation by 4-HPR occurs through the activation of a signaling cascade starting from increase of ROS generation, leading to induction of endoplasmic reticulum (ER) stress response and Jun N-terminal Kinase (JNK) activation [9], [10]. From the analysis of plasma samples of 4-HPR-treated patients, we have identified a new 4-HPR polar metabolite, 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) [11], which is endowed with promising biological properties [12].…”

Section: Introductionmentioning

confidence: 99%

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4-oxo-N-(4-hydroxyphenyl)retinamide: Two Independent Ways to Kill Cancer Cells

et al. 2010

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BackgroundThe retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) is a polar metabolite of fenretinide (4-HPR) very effective in killing cancer cells of different histotypes, able to inhibit 4-HPR-resistant cell growth and to act synergistically in combination with the parent drug. Unlike 4-HPR and other retinoids, 4-oxo-4-HPR inhibits tubulin polymerization, leading to multipolar spindle formation and mitotic arrest. Here we investigated whether 4-oxo-4-HPR, like 4-HPR, triggered cell death also via reactive oxygen species (ROS) generation and whether its antimicrotubule activity was related to a ROS-dependent mechanism in ovarian (A2780), breast (T47D), cervical (HeLa) and neuroblastoma (SK-N-BE) cancer cell lines.Methodology/Principal FindingsWe provided evidence that 4-oxo-4-HPR, besides acting as an antimicrotubule agent, induced apoptosis through a signaling cascade starting from ROS generation and involving endoplasmic reticulum (ER) stress response, Jun N-terminal Kinase (JNK) activation, and upregulation of the proapoptotic PLAcental Bone morphogenetic protein (PLAB). Through time-course analysis and inhibition of the ROS-related signaling pathway (upstream by vitamin C and downstream by PLAB silencing), we demonstrated that the antimitotic activity of 4-oxo-4-HPR was independent from the oxidative stress induced by the retinoid. In fact, ROS generation occurred earlier than mitotic arrest (within 30 minutes and 2 hours, respectively) and abrogation of the ROS-related signaling pathway did not prevent the 4-oxo-4-HPR-induced mitotic arrest.Conclusions/SignificanceThese data indicate that 4-oxo-4-HPR anticancer activity is due to at least two independent mechanisms and provide an explanation of the ability of 4-oxo-4-HPR to be more potent than the parent drug and to be effective also in 4-HPR-resistant cell lines. In addition, the double mechanism of action could allow 4-oxo-4-HPR to efficiently target tumour and to eventually counteract the development of drug resistance.

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Section: Resultsmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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4-oxo-N-(4-hydroxyphenyl)retinamide: Two Independent Ways to Kill Cancer Cells

et al. 2010

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“…As discussed earlier (Section 5.8), MIC-1 was identified by transcriptome profiling of ovarian carcinoma cells as highly induced by FEN and associated with FEN-induced apoptosis in several cell lines [57]. Thus, FEN-induced MIC-1 up-regulation may mediate some of the anti-obesity effects of FEN treatment since overproduction of MIC-1 by tumors has been reported to contribute to tumor-induced anorexia and weight-loss in mice [60].…”

Section: Fen-induced Ra-like Effects On Energy Balance and Glucose Homentioning

confidence: 96%

“…Macrophage inhibitory cytokine-1 (MIC-1), a proapoptotic and antiangiogenic gene, was the most highly induced [56,57]. MIC-1 levels were highly associated with FENinduced apoptosis in several cell lines and were also induced in ascitic cells collected from patients with ovarian cancer before and after FEN treatment.…”

Section: Mic-1/plab/nag-1/gdf-15mentioning

confidence: 96%

The mechanisms of Fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes

Mody

Mcilroy

2014

Biochemical Pharmacology

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Fenretinide remains the most investigated retinoid compound for the prevention of cancer. Its clinical use remains a genuine possibility due to a favourable toxicological profile and accumulation in fatty tissues. Like other well-characterised pharmacological therapies, Fenretinide has been shown to affect multiple signalling pathways. Recent findings have discovered additional beneficial properties the synthetic retinoid was not intentionally designed for, including the prevention of high-fat diet-induced obesity and insulin resistance. These preclinical findings in rodents are timely since obesity has reached pandemic proportions and safe effective therapeutics are severely lacking. Recent investigations have proposed various mechanisms of action for the beneficial effects of Fenretinide. This review covers the current knowledge about Fenretinide's use as a therapy for cancer and potential to treat obesity, insulin resistance and glucose intolerance. An overview of the signalling pathways manipulated by Fenretinide including retinoid homeostasis, reactive oxygen species generation and inhibition of ceramide synthesis will be presented and insights into apoptosis and/or autophagy induction by Fenretinide will also be discussed. The largely unexplored area of Fenretinide metabolites as alternative therapeutic options and how these may be relevant will also be presented. Fenretinide shows great promise, but unfortunately evidence is lacking from clinical trials on Fenretinide's effectiveness in humans. Finally we identify what action can be taken to further progress the investigation of this extremely important retinoid.

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Retinoids

Dawson¹

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retinoid drugs find major applications in the topical treatment of cutaneous proliferative disorders such as acne, psoriasis, and photoaging and cutaneous cancers such as cutaneous T‐cell lymphoma (CTCL) and Kaposi's sarcoma. Oral retinoids are successfully used to treat nodular/cystic acne, systemic CTCL, and acute promyelocytic leukemia. This overview of available retinoid drugs and those in the preclinical or clinical pipeline covers their development, indications, clinical trial results, adverse effects, and pharmacology/metabolism. Retinoids have been described historically and functionally in the context of interaction with their nuclear receptors—retinoic acid receptors (RARs) and retinoid X receptors (RXRs)—in inducing gene transcription. RAR‐selective retinoids or their prodrugs include first‐generation all‐ trans ‐retinoic acid (tretinoin) and its 13‐ cis isomer (isotretinoin), and second‐generation acitretin and its ethyl ester (etretinate), both having an aromatic 2,3,6‐trimethyl‐4‐methoxyphenyl terminus. Third‐generation more aromatic analogs include ethyl ester tazarotene (Tazorac®) and adapalene (Differin®), both selective for RAR subtypes β and γ, and RARα‐selective pipeline candidates Am80 and NRX 195183, which are in clinical trials. RAR and RXR transcriptional panagonist 9‐ cis ‐retinoic acid is next and is followed by RXR‐selective bexarotene (Targretin™) and two RXR‐selective clinical trial candidates, 9cUAB and NRX 194204. The fourth generation includes three compounds that may have applications in the treatment or prevention of cancer. While originally considered as retinoids, such as N ‐(4‐hydroxyphenyl) retinamide, or as retinoid‐related or derived, such as ST1926 (AHPC) and SHetA2, they subsequently were found to function independently of the RARs and RXRs in inhibiting cancer cell proliferation and inducing apoptosis.

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Analysis of gene expression identifies PLAB as a mediator of the apoptotic activity of fenretinide in human ovarian cancer cells

Cited by 14 publications

References 34 publications

4-oxo-N-(4-hydroxyphenyl)retinamide: Two Independent Ways to Kill Cancer Cells

4-oxo-N-(4-hydroxyphenyl)retinamide: Two Independent Ways to Kill Cancer Cells

The mechanisms of Fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes

Retinoids

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