Isoprenylcysteine carboxylmethyltransferase is associated with nasopharyngeal carcinoma chemoresistance and Ras activation

Zhu, Yanjun; Hu, Qiyan; Li, Hui

doi:10.1016/j.bbrc.2019.06.074

Cited by 7 publications

(9 citation statements)

References 26 publications

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“…The ZNF24-SLC7A5 signaling axis established in this study further explains the oncogenic mechanism of SLC7A5. In view of the urgent need for in-depth exploration of downstream targets of Ras to address the difficult problem of Ras targeting ( 27 , 28 ) and drug resistance in the treatment of Ras mutant LUAD ( 29 – 31 ), the elucidation of ZNF24 greatly aids research on the above problems.…”

Section: Discussionmentioning

confidence: 99%

ZNF24 regulates the progression of KRAS mutant lung adenocarcinoma by promoting SLC7A5 translation

Jia

Wang³

et al. 2022

Front. Oncol.

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BackgroundClinical treatment of RAS mutant cancers is challenging because of the complexity of the Ras signaling pathway. SLC7A5 is a newly discovered downstream gene of the Ras signaling pathway, but the regulatory mechanism is unclear. We aimed to explore the molecular mechanism and role in KRAS mutant lung adenocarcinoma progression.MethodsKey gene that regulated SLC7A5 in KRAS mutant lung adenocarcinoma was screened by RNA sequencing and bioinformatics analysis. The effect of this gene on the expression of SLC7A5 was studied by RNAi. The regulatory mechanism between the two genes was investigated by immunofluorescence, CoIP, pulldown and yeast two-hybrid assays. The location of the two genes was determined by inhibiting Ras and the downstream pathways PI3K-AKT and MEK-ERK. By in vivo and in vitro experiments, the effects of the key gene on the biological functions of KRAS mutant lung adenocarcinoma were explored.ResultsWe found a novel gene, ZNF24, which upregulated SLC7A5 protein expression rather than mRNA expression in KRAS mutant lung adenocarcinoma. Endogenous protein interactions occurred between ZNF24 and SLC7A5. Ras inhibition reduced the expression of ZNF24 and SLC7A5. ZNF24 and SLC7A5 are located downstream of the MEK-ERK and PI3K-AKT pathways. In vivo and in vitro functional experiments confirmed that the ZNF24-SLC7A5 signaling axis promoted the proliferation, invasion and migration of KRAS mutant lung adenocarcinoma.ConclusionsZNF24 promoted the growth of KRAS mutant lung adenocarcinoma by upregulating SLC7A5 protein expression, which suggested that ZNF24 is a new biomarker of KRAS mutant tumors and could be a new potential therapeutic target for Ras-driven tumors.

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Section: Discussionmentioning

confidence: 99%

ZNF24 regulates the progression of KRAS mutant lung adenocarcinoma by promoting SLC7A5 translation

Jia

Wang³

et al. 2022

Front. Oncol.

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“…Isoprenylated cysteine analogs inhibited ICMT activity and showed antiproliferative effects, however, their mechanism of action is not clear since some of them act as modulators of RAS chaperones ( 107 , 108 ). Indole-based molecules were also proposed, such as Cysmethynil ( 109 ), a competitive inhibitor with respect to isoprenylated cysteine and a non-competitive inhibitor with respect to SAM, which showed antitumor activity in vitro and in vivo ( 10 , 110 , 111 ). In summary, alteration of MVA pathway and protein prenylation by mutant p53 revealed interesting connections to explore.…”

Section: Discussionmentioning

confidence: 99%

Beyond the Mevalonate Pathway: Control of Post-Prenylation Processing by Mutant p53

et al. 2020

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Missense mutations in the TP53 gene are among the most frequent alterations in human cancer. Consequently, many tumors show high expression of p53 point mutants, which may acquire novel activities that contribute to develop aggressive tumors. An unexpected aspect of mutant p53 function was uncovered by showing that some mutants can increase the malignant phenotype of tumor cells through alteration of the mevalonate pathway. Among metabolites generated through this pathway, isoprenoids are of particular interest, since they participate in a complex process of posttranslational modification known as prenylation. Recent evidence proposes that mutant p53 also enhances this process through transcriptional activation of ICMT, the gene encoding the methyl transferase responsible for the last step of protein prenylation. In this way, mutant p53 may act at different levels to promote prenylation of key proteins in tumorigenesis, including several members of the RAS and RHO families. Instead, wild type p53 acts in the opposite way, downregulating mevalonate pathway genes and ICMT. This oncogenic circuit also allows to establish potential connections with other metabolic pathways. The demand of acetyl-CoA for the mevalonate pathway may pose limitations in cell metabolism. Likewise, the dependence on S-adenosyl methionine for carboxymethylation, may expose cells to methionine stress. The involvement of protein prenylation in tumor progression offers a novel perspective to understand the antitumoral effects of mevalonate pathway inhibitors, such as statins, and to explore novel therapeutic strategies.

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“…All compounds were reconstituted according to the manufacturer's instructions and stored at −20 °C in aliquots. Transfections of ICMT siRNA were performed using the same protocol as described in our previous study [4].…”

Section: Cell Culture Compounds and Transfectionmentioning

confidence: 99%

Inhibition of mitochondrial function by approved drugs overcomes nasopharyngeal carcinoma chemoresistance

Zhang,

Guo,

Zhu

et al. 2024

Anti-Cancer Drugs

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The development of chemo-resistance in nasopharyngeal carcinoma (NPC) presents a significant therapeutic challenge, and its underlying mechanisms remain poorly understood. In our previous studies, we highlighted the association between isoprenylcysteine carboxylmethyltransferase (ICMT) and chemoresistance in NPC. In this current research, we revealed that both 5-FU and cisplatin-resistant NPC cells exhibited elevated mitochondrial function and increased expression of mitochondrial genes, independent of ICMT. Our investigations further showed that classic mitochondrial inhibitors, such as oligomycin, antimycin, and rotenone, were notably more effective in reducing viability in chemo-resistant NPC cells compared to parental cells. Moreover, we identified two antimicrobial drugs, tigecycline and atovaquone, recognized as mitochondrial inhibitors, as potent agents for decreasing chemo-resistant NPC cells by targeting mitochondrial respiration. Remarkably, tigecycline and atovaquone, administered at tolerable doses, inhibited chemo-resistant NPC growth in mouse models and extended overall survival rates. This work unveils the efficacy of mitochondrial inhibition as a promising strategy to overcome chemo-resistance in NPC. Additionally, our findings highlight the potential repurposing of clinically available drugs like tigecycline and atovaquone for treating NPC patients who develop chemoresistance.

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Isoprenylcysteine carboxylmethyltransferase is associated with nasopharyngeal carcinoma chemoresistance and Ras activation

Cited by 7 publications

References 26 publications

ZNF24 regulates the progression of KRAS mutant lung adenocarcinoma by promoting SLC7A5 translation

ZNF24 regulates the progression of KRAS mutant lung adenocarcinoma by promoting SLC7A5 translation

Beyond the Mevalonate Pathway: Control of Post-Prenylation Processing by Mutant p53

Inhibition of mitochondrial function by approved drugs overcomes nasopharyngeal carcinoma chemoresistance

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