Caffeic acid phenethyl ester targets ubiquitin-specific protease 8 and synergizes with cisplatin in endometrioid ovarian carcinoma cells

Colombo, Diego; Gatti, Laura; Sjöstrand, Linda; Carenini, Nives; Costantino, Matteo; Corna, Elisabetta; Arrighetti, Noemi; Zuccolo, Marco; Cesare, Michelandrea De; Linder, Stig; D’Arcy, Pádraig; Perego, Paola

doi:10.1016/j.bcp.2021.114900

Cited by 5 publications

(4 citation statements)

References 47 publications

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“…Indeed, embryonic lethality has been observed in USP8 knockout mice (Dufner and Knobeloch, 2019). In a recent study, we observed a variable expression of USP8 across ovarian cancer cell lines and found a synergistic interaction between cisplatin and caffeic acid phenethyl ester, identified as USP8 inhibitor, in endometrioid ovarian carcinoma cells expressing high levels of USP8, thereby suggesting the opportunity to carry out a molecular targeting of USP8 in such a disease (Colombo et al, 2022). Thus, the present study was designed to examine the contribution of USP8 to drug resistance and response to cisplatin given the possible interplay of USP8 with survival pathways.…”

Section: Discussionmentioning

confidence: 93%

“…In this context, a report by Byun S et al suggests USP8 as a novel therapeutic target for overcoming gefitinib resistance in lung cancer, specifically involving USP8 in EGF-R signaling ( Byun et al, 2013 ). Besides, a synergistic interaction between cisplatin and caffeic acid phenethyl ester, capable to inhibit USP8, has been observed in endometrioid ovarian carcinoma cells ( Colombo et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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The deubiquitinase USP8 regulates ovarian cancer cell response to cisplatin by suppressing apoptosis

Corno¹,

D’Arcy

Bagnoli³

et al. 2022

Front. Cell Dev. Biol.

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The identification of therapeutic approaches to improve response to platinum-based therapies is an urgent need for ovarian carcinoma. Deubiquitinases are a large family of ubiquitin proteases implicated in a variety of cellular functions and may contribute to tumor aggressive features through regulation of processes such as proliferation and cell death. Among the subfamily of ubiquitin-specific peptidases, USP8 appears to be involved in modulation of cancer cell survival by still poorly understood mechanisms. Thus, we used ovarian carcinoma cells of different histotypes, including cisplatin-resistant variants with increased survival features to evaluate the efficacy of molecular targeting of USP8 as a strategy to overcome drug resistance/modulate cisplatin response. We performed biochemical analysis of USP8 activity in pairs of cisplatin-sensitive and -resistant cells and found increased USP8 activity in resistant cells. Silencing of USP8 resulted in decreased activation of receptor tyrosine kinases and increased sensitivity to cisplatin in IGROV-1/Pt1 resistant cells as shown by colony forming assay. Increased cisplatin sensitivity was associated with enhanced cisplatin-induced caspase 3/7 activation and apoptosis, a phenotype also observed in cisplatin sensitive cells. Increased apoptosis was linked to FLIPL decrease and cisplatin induction of caspase 3 in IGROV-1/Pt1 cells, cisplatin-induced claspin and survivin down-regulation in IGROV-1 cells, thereby showing a decrease of anti-apoptotic proteins. Immunohistochemical staining on 65 clinical specimens from advanced stage ovarian carcinoma indicated that 40% of tumors were USP8 positive suggesting that USP8 is an independent prognostic factor for adverse outcome when considering progression free survival as a clinical end-point. Taken together, our results support that USP8 may be of diagnostic value and may provide a therapeutic target to improve the efficacy of platinum-based therapy in ovarian carcinoma.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

The deubiquitinase USP8 regulates ovarian cancer cell response to cisplatin by suppressing apoptosis

Corno¹,

D’Arcy

Bagnoli³

et al. 2022

Front. Cell Dev. Biol.

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“…Furthermore, ovarian cancer OV7 cells were treated with 5–100 µM of CAPE to explore its therapeutic benefits in serous ovarian cancer ( 30 ). In a separate study, endometrioid ovarian carcinoma cells were exposed to CAPE at concentrations ranging from 1–10 µM, demonstrating its anti-tumorigenic activity ( 31 ). It was also revealed that CAPE at concentrations ranging from 1–50 µM could induce apoptosis and oxidative stress in human multiple myeloma cells ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Caffeic acid phenethyl ester: Unveiling its potential as a potent apoptosis inducer for combating hypopharyngeal squamous cell carcinoma

Kim,

Ahn,

Shin

et al. 2023

Oncol Rep

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Hypopharyngeal squamous cell carcinoma (HSCC) is a relatively rare form of head and neck cancer that is notorious for its poor prognosis and low overall survival rate. This highlights the need for new therapeutic options for this malignancy. The objective of the present study was to examine the ability of caffeic acid phenethyl ester (CAPE), which is an active compound found in propolis, to combat HSCC tumor growth. CAPE exerted its tumor-suppressive activity in HSCC cell lines through the induction of apoptosis. Mechanistically, the CAPE-mediated apoptotic process was attributed to the perturbation of the mitochondrial membrane potential and the activation of caspase-9. CAPE also modulated survivin and X-linked inhibitor of apoptosis, which are potent members of the inhibitors of apoptosis protein family, either through transcriptional or post-translational regulation, leading to HSCC cell line death. Therefore, the findings of the present study suggested that CAPE is an effective treatment alternative for HSCC via the stimulation of mitochondria-dependent apoptosis.

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“…The chemical requirements for inhibition of DUBs are shared by curcumin and most related compounds including CAPE. In fact, a recent study support that CAPE can inihibit the DUB ubiquitin-specific protease 8, but not proteasome associated DUBs in cell-free assays, suggesting partial selectivity ( Colombo et al, 2022 ). CAPE, similarly to what observed for curcumin, has also been shown to reduce 26S proteasome proteolytic activities, mainly affecting chymotrypsin-like activity ( Matsunaga et al, 2019 ).…”

Section: Mechanism Of Action Of Curcumin and Related Compoundsmentioning

confidence: 99%

Curcumin and Related Compounds in Cancer Cells: New Avenues for Old Molecules

et al. 2022

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Curcumin and related compounds are known for the large spectrum of activities. The chemical features of these compounds are important for their biological effects with a key role for the thiol-reactive α−β unsaturated carbonyl groups. Curcumin derivatives may overcome the limitation of the bioavailability of the parent compound, while maintaining the key chemical features responsible for biological activities. Curcumin and related compounds show anti-viral, anti-fungal, anti-microbial and anti-tumor activities. The therapeutic effects of curcumin, used as a supplement in cancer therapy, have been documented in various cancer types, in which inhibition of cell growth and survival pathways, induction of apoptosis and other cell death pathways have been reported. Curcumin-induced apoptosis has been linked both to the intrinsic and extrinsic apoptotic pathways. Necroptosis has also been involved in curcumin-induced toxicity. Among curcumin-induced effects, ferroptosis has also been described. The mechanism of curcumin toxicity can be triggered by reactive oxygen species-mediated endoplasmic reticulum stress. Curcumin targets have been identified in the context of the ubiquitin-proteasome system with evidence of inhibition of the proteasome proteolytic activities and cellular deubiquitinases. Curcumin has recently been shown to act on the tumor microenvironment with effects on cancer-associated fibroblasts and immune cells. The related product caffeic acid phenethyl ester has shown promising preclinical results with an effect on the inflammatory microenvironment. Here, we review the mechanisms underlying curcumin and derivatives toxicity towards cancer cells with particular emphasis on cell death pathways and the ubiquitin-proteasome system.

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Caffeic acid phenethyl ester targets ubiquitin-specific protease 8 and synergizes with cisplatin in endometrioid ovarian carcinoma cells

Cited by 5 publications

References 47 publications

The deubiquitinase USP8 regulates ovarian cancer cell response to cisplatin by suppressing apoptosis

The deubiquitinase USP8 regulates ovarian cancer cell response to cisplatin by suppressing apoptosis

Caffeic acid phenethyl ester: Unveiling its potential as a potent apoptosis inducer for combating hypopharyngeal squamous cell carcinoma

Curcumin and Related Compounds in Cancer Cells: New Avenues for Old Molecules

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