Identification of a Novel Potent CYP4Z1 Inhibitor Attenuating the Stemness of Breast Cancer Cells through Lead Optimization

Yin, Yuan; Yao, Hong; Zhou, Manzhen; Ma, Xiaoqian; Zhou, Yi; Xu, Jinyi; Niu, Miaomiao; Yin, Jun; Zheng, Lufeng; Xu, Shengtao

doi:10.1021/acs.jmedchem.2c01320

Cited by 5 publications

(2 citation statements)

References 38 publications

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“…This 'suicide gene' strategy was further refined recently by Hanenberg's group for application in adoptive T-cell therapies using a highly active modified human CYP4B1 (Roellecke et al, 2016). Today, attention in this area has turned increasingly towards CYP4Z1 as the target for enzyme inhibitors (Kowalski et al, 2020 a ;Machalz et al, 2021;Yuan et al, 2022), and potentially as a protoxin activating CYP in breast cancer. There and back again indeed!…”

Section: Discussionmentioning

confidence: 99%

There and Back Again: A Perspective on 20 Years of CYP4Z1

Kowalski,

Rettie

2024

Drug Metab Dispos

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Abbreviations14,15-dihydroxy eicosatrienoic acid (14,15-DiHET); 1-aminobenzotriazole (ABT); 1-benzylimidazole (1BI); 20hydroxyeicosatetraenoic acid (20-HETE); 3-((4-(1H-imidazol-1-yl)benzamido)methyl)benzoic acid (inhibitor 9); 8-[(1H-benzotriazol-1-yl)amino]octanoic acid (8-BOA); arachidonic acid (AA); competing endogenous RNA (ceRNA); cytochrome P450 (CYP); cytochrome P450 reductase (CPR); epidermal growth factor (EGF); epoxyeicosatrienoic acid (EET); estrogen receptor alpha (ERα); ethyl (E)-4-(4-(N'hydroxyformimidamido)phenyl)butanoate (7c); fibroblast growth factor (FGF); gas chromatography-mass spectrometry (GC-MS); lauric acid (LA); liquid chromatography with tandem mass spectrometry (LC-MS/MS); luciferin-4F12 (Luc-4F12); luciferin-benzyl ether (Luc-BE); mechanism-based inactivator (MBI); mitogenactivated protein kinase (MAPK); myristic acid (MA); N-hydroxy-N'-(-butyl-2-methylphenyl)-formamidine (HET0016); nickel nitrilotriacetic (Ni-NTA); phosphoinositide 3-kinase/protein kinase B (PI3K/Akt); plateletderived growth factor (PDGF); polyunsaturated fatty acid (PUFA); soluble epoxide hydrolase (sEH); timedependent inhibition (TDI); triple negative negative breast cancer (TNBC); vascular endothelial growth factor (VEGF) Pages and Word Count

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Section: Discussionmentioning

confidence: 99%

There and Back Again: A Perspective on 20 Years of CYP4Z1

Kowalski,

Rettie

2024

Drug Metab Dispos

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“…Furthermore, CSCs have been found to have immunomodulatory activity as CSCs have been shown to exhibit the immunotherapeutic resistance. According to these characteristics, CSCs play an irreplaceable role in the treatment of malignant tumors as our previous studies have shown targeting CSCs can significantly suppress tumor migration, invasion, and drug resistance [32][33][34]. Epigenetics plays an important role in maintaining the above biological characteristics of CSCs, which refers to the phenomenon that the DNA sequence has not changed but the traits have heritable changes.…”

Section: The Effects Of M 6 A-rna Modification On Csc Progressionmentioning

confidence: 99%

The roles of m6A RNA methylation modification in cancer stem cells: new opportunities for cancer suppression

Chen

Shi

et al. 2022

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As a reversible post-transcriptional modification, N6-methyladeno sine is the most common form of RNA modification in eukaryotic mRNA. Cancer stem cells (CSCs), which are a subpopulation of cells with self-renewal ability and differentiation potential, have been regarded to be one of the roots of tumor occurrence, recurrence, and metastasis. Currently, numerous studies have demonstrated that m6A RNA modification is critically implicated in the regulation of CSCs stemness or the CSC-like traits of cancer cells. This review summarized the effects of m6A RNA modification-related enzymes and underlying mechanisms contributing to CSCs or cancer cell stemness, which may provide novel targets and research directions for the specifical elimination of CSCs or cancer cells with stemness.

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Engrailed 2 facilitates progression of triple-negative and HER2-enriched breast cancer by binding to enhancer region of Tenascin-C

Chen,

Yin

2024

Discov Onc

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Engrailed 2 (EN2) is a homeodomain-containing protein whose aberrant expression is observed in various cancer types, yet its role in breast cancer remains unclear. This study investigates the roles and mechanisms of EN2 in breast cancer progression. Using online dataset analysis, we assessed the correlation between EN2 expression and breast cancer progression and chemotherapeutic sensitivity. Functional assays, including RT-qPCR, Western blot, cell viability, transwell migration and invasion, spheroid formation, and flow cytometry, were conducted to explore EN2's role. Mechanistic insights were obtained through luciferase reporter assays, ChIP, and Caspase 3 activity detection. Our results showed that EN2 is highly expressed in breast cancer patients, negatively correlating with survival rates and positively with disease progression and reduced chemotherapy sensitivity. Functional experiments confirmed EN2's oncogenic role, and it was found to promote the expression of the oncogenic Tenascin-C (TNC) gene. Notably, EN2 directly interacts with the super-enhancer region within the TNC locus. Elevated TNC expression mitigated the effects of EN2 knockdown on breast cancer cell progression. Our study unveils a novel mechanism by which EN2 regulates the TNC locus super-enhancer, thereby activating oncogenic pathways in breast cancer. Supplementary Information The online version contains supplementary material available at 10.1007/s12672-024-01471-6.

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Identification of a Novel Potent CYP4Z1 Inhibitor Attenuating the Stemness of Breast Cancer Cells through Lead Optimization

Cited by 5 publications

References 38 publications

There and Back Again: A Perspective on 20 Years of CYP4Z1

There and Back Again: A Perspective on 20 Years of CYP4Z1

The roles of m6A RNA methylation modification in cancer stem cells: new opportunities for cancer suppression

Engrailed 2 facilitates progression of triple-negative and HER2-enriched breast cancer by binding to enhancer region of Tenascin-C

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