AKR1C3 is a biomarker and druggable target for oropharyngeal tumors

Peraldo-Neia, Caterina; Ostano, Paola; Mello-Grand, Maurizia; Guana, Francesca; Gregnanin, Ilaria; Boschi, Donatella; Oliaro‐Bosso, Simonetta; Pippione, Agnese Chiara; Carenzo, Andrea; Cecco, Loris De; Cavalieri, Stefano; Micali, Arianna; Perrone, Federica; Averono, Gianluca; Bagnasacco, Paolo; Dosdegani, R; Masini, Laura; Krengli, Marco; Aluffi-Valletti, Paolo; Valente, Guido; Chiorino, Giovanna

doi:10.1007/s13402-020-00571-z

Cited by 14 publications

(11 citation statements)

References 59 publications

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“…A series of derivatives with lipophilic substituents on the C-4 position were prepared and could be divided into subgroups depending on the nature of the C-6 substituent, which was either a phenol function (20)(21)(22)26) or a methoxy group (27 and 28). The latter analogues of 18 bearing electron-rich substituents in C-4 position (R 4 = Cl for 27 or R 4 = F for 28) were both inactive at 10 µM (26.1% and 20.3% inhibition, respectively).…”

Section: Discussionmentioning

confidence: 99%

“…As regulators of hormone signalling, steroid-metabolising enzymes are important in several biological processes, e.g., sexual development, reproduction, and maintenance of energy level or response to stress, and changes in their enzymatic activities can lead to serious diseases. Indeed, AKR1C3 is associated with several diseases such as prostate cancer [18], breast cancer [7], endometrial cancer [17], cervical cancer [17], endometriosis [19], non-small cell lung cancer [20], colorectal cancer [21], oropharyngeal tumour [22], leukaemia [23], gastric cancer [24], etc. [25].…”

Section: Introductionmentioning

confidence: 99%

“…Our current research aimed to further explore and clarify the importance of the substitution pattern on the inhibitory activity against AKR1C3 for a set of 12 synthetic chalcones (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29), along with isoliquiritigenin (16) and butein (17) obtained from commercial sources. Our goal was to better understand the AKR1C3-chalcone interaction and to develop an efficient chalcone-based AKR1C3 inhibitor.…”

Section: Introductionmentioning

confidence: 99%

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Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3

et al. 2022

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Naturally occurring substances are valuable resources for drug development. In this respect, chalcones are known to be antiproliferative agents against prostate cancer cell lines through various mechanisms or targets. Based on the literature and preliminary results, we aimed to study and optimise the efficiency of a series of chalcones to inhibit androgen-converting AKR1C3, known to promote prostate cancer. A total of 12 chalcones with different substitution patterns were synthesised. Structure–activity relationships associated with these modifications on AKR1C3 inhibition were analysed by performing enzymatic assays and docking simulations. In addition, the selectivity and cytotoxicity of the compounds were assessed. In enzymatic assays, C-6′ hydroxylated derivatives were more active than C-6′ methoxylated derivatives. In contrast, C-4 methylation increased activity over C-4 hydroxylation. Docking results supported these findings with the most active compounds fitting nicely in the binding site and exhibiting strong interactions with key amino acid residues. The most effective inhibitors were not cytotoxic for HEK293T cells and selective for 17β-hydroxysteroid dehydrogenases not primarily involved in steroid hormone metabolism. Nevertheless, they inhibited several enzymes of the steroid metabolism pathways. Favourable substitutions that enhanced AKR1C3 inhibition of chalcones were identified. This study paves the way to further develop compounds from this series or related flavonoids with improved inhibitory activity against AKR1C3.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3

et al. 2022

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“…AKR1C3, a member of the aldo‐keto reductase (AKR) superfamily, has multiple cellular functions in regulating prostaglandin, steroid hormone, and retinoid metabolism 6 . AKR1C3 has been reported to be significantly associated with the progression and prognosis of many tumors 7,8 . AKR1C3 is involved in the regulation of a variety of cancer‐related biological processes, including proliferation, epithelial−mesenchymal transition, as well as chemosensitivity 9,10 .…”

Section: Introductionmentioning

confidence: 99%

“…6 AKR1C3 has been reported to be significantly associated with the progression and prognosis of many tumors. 7,8 AKR1C3 is involved in the regulation of a variety of cancerrelated biological processes, including proliferation, epithelial−mesenchymal transition, as well as chemosensitivity. 9,10 In our previous study, we found that AKR1C3 was significantly upregulated in HCC and that increased AKR1C3 was associated with poor survival in patients with HCC.…”

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confidence: 99%

AKR1C3 suppresses ferroptosis in hepatocellular carcinoma through regulation of YAP/SLC7A11 signaling pathway

Chen

Zhang

Tian

et al. 2023

Molecular Carcinogenesis

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AKR1C3 is frequently overexpressed and it is a validated therapeutic target in various tumors including hepatocellular carcinoma (HCC). Our previous study showed that AKR1C3 facilitated HCC proliferation and metastasis by forming a positive feedback loop of AKR1C3-NF-κB-STAT3. Ferroptosis is a form of irondependent cell death driven by iron-dependent accumulation of lipid reactive oxygen species and plays an important role in tumor suppression. However, little is known about the role of AKR1C3 in ferroptosis susceptibility. In this study, we found that knockdown of AKR1C3 potently enhanced the sensitivity of HCC cells to ferroptosis inducers both in vitro and in vivo. Overexpression of AKR1C3 protected against ferroptosis in HCC cells. Mechanistically, AKR1C3 regulated ferroptosis through YAP/SLC7A11 signaling in HCC. AKR1C3 knockdown led to a decrease in YAP nuclear translocation, resulted in the inhibition of cystine transporter SLC7A11, and a subsequent increase in the intracellular levels of ferrous iron and ultimately ferroptosis. Moreover, we found that the combination of AKR1C3 and SLC7A11 was a strong predictor of poor prognosis in HCC. Collectively, these findings identify a novel role of AKR1C3 in ferroptosis, and highlighting a candidate therapeutic target to potentially improve the effect of ferroptosis-based antitumor therapy.

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Fenamates: Forgotten treasure for cancer treatment and prevention: Mechanisms of action, structural modification, and bright future

Li,

Wang,

Zhang

et al. 2024

Medicinal Research Reviews

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Fenamates as classical nonsteroidal anti‐inflammatory agents are widely used for relieving pain. Preclinical studies and epidemiological data highlight their chemo‐preventive and chemotherapeutic potential for cancer. However, comprehensive reviews of fenamates in cancer are limited. To accelerate the repurposing of fenamates, this review summarizes the results of fenamates alone or in combination with existing chemotherapeutic agents. This paper also explores targets of fenamates in cancer therapy, including COX, AKR family, AR, gap junction, FTO, TEAD, DHODH, TAS2R14, ion channels, and DNA. Besides, this paper discusses other mechanisms, such as regulating Wnt/β‐catenin, TGF‐β, p38 MAPK, and NF‐κB pathway, and the regulation of the expressions of Sp, EGR‐1, NAG‐1, ATF‐3, ErbB2, AR, as well as the modulation of the tumor immune microenvironment. Furthermore, this paper outlined the structural modifications of fenamates, highlighting their potential as promising leads for anticancer drugs.

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AKR1C3 is a biomarker and druggable target for oropharyngeal tumors

Cited by 14 publications

References 59 publications

Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3

Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3

AKR1C3 suppresses ferroptosis in hepatocellular carcinoma through regulation of YAP/SLC7A11 signaling pathway

Fenamates: Forgotten treasure for cancer treatment and prevention: Mechanisms of action, structural modification, and bright future

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