Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications

Lu, Jia; Chen, Siwei; Bai, Xuejiao; Liao, Minru; Qiu, Yuling; Zheng, Ling-Li; Yu, Haiyang

doi:10.1016/j.bcp.2023.115907

Cited by 13 publications

(2 citation statements)

References 165 publications

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“…Increased cholesterol metabolism in ρ 0 D5 cells provides metastatic cancer cells with much needed cholesterol as a structural element of membranes. However, cholesterol and its derivates such as oxysterol, also promote cancer stemness, chronic inflammation and pro-tumour signalling pathways, such as MAPK and Wnt/b-catenin pathways and activation of STAT-3, which promotes EMT ( 38 , 39 ).…”

Section: Discussionmentioning

confidence: 99%

Residual OXPHOS is required to drive primary and metastatic lung tumours in an orthotopic breast cancer model

Herst,

Carson,

Lewthwaite

et al. 2024

Front. Oncol.

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BackgroundFast adaptation of glycolytic and mitochondrial energy pathways to changes in the tumour microenvironment is a hallmark of cancer. Purely glycolytic ρ0 tumour cells do not form primary tumours unless they acquire healthy mitochondria from their micro-environment. Here we explored the effects of severely compromised respiration on the metastatic capability of 4T1 mouse breast cancer cells.Methods4T1 cell lines with different levels of respiratory capacity were generated; the Seahorse extracellular flux analyser was used to evaluate oxygen consumption rates, fluorescent confocal microscopy to assess the number of SYBR gold-stained mitochondrial DNA nucleoids, and the presence of the ATP5B protein in the cytoplasm and fluorescent in situ nuclear hybridization was used to establish ploidy. MinION nanopore RNA sequence analysis was used to compare mitochondrial DNA transcription between cell lines. Orthotopic injection was used to determine the ability of cells to metastasize to the lungs of female Balb/c mice.ResultsOXPHOS-deficient ATP5B-KO3.1 cells did not generate primary tumours. Severely OXPHOS compromised ρ0D5 cells generated both primary tumours and lung metastases. Cells generated from lung metastasis of both OXPHOS-competent and OXPHOS-compromised cells formed primary tumours but no metastases when re-injected into mice. OXPHOS-compromised cells significantly increased their mtDNA content, but this did not result in increased OXPHOS capacity, which was not due to decreased mtDNA transcription. Gene set enrichment analysis suggests that certain cells derived from lung metastases downregulate their epithelial-to-mesenchymal related pathways.ConclusionIn summary, OXPHOS is required for tumorigenesis in this orthotopic mouse breast cancer model but even very low levels of OXPHOS are sufficient to generate both primary tumours and lung metastases.

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Section: Discussionmentioning

confidence: 99%

Residual OXPHOS is required to drive primary and metastatic lung tumours in an orthotopic breast cancer model

Herst,

Carson,

Lewthwaite

et al. 2024

Front. Oncol.

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“…392 Cancers such as gastric cancer, pancreatic cancer, and colon cancer, which exhibit dysregulated lipid metabolism and rely on the mevalonate pathway, highlight the potential of repurposing statin drugs for treating various cancers. [393][394][395] However, the diversity of cancers is equally important. Different cancer types have distinct genetic backgrounds, biomarkers, and microenvironment interactions, leading to varying responses to the same drug.…”

Section: Challenges Of Drug Repurposingmentioning

confidence: 99%

Drug repurposing for cancer therapy

Xia,

Sun,

Huang

et al. 2024

Sig Transduct Target Ther

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Cancer, a complex and multifactorial disease, presents a significant challenge to global health. Despite significant advances in surgical, radiotherapeutic and immunological approaches, which have improved cancer treatment outcomes, drug therapy continues to serve as a key therapeutic strategy. However, the clinical efficacy of drug therapy is often constrained by drug resistance and severe toxic side effects, and thus there remains a critical need to develop novel cancer therapeutics. One promising strategy that has received widespread attention in recent years is drug repurposing: the identification of new applications for existing, clinically approved drugs. Drug repurposing possesses several inherent advantages in the context of cancer treatment since repurposed drugs are typically cost-effective, proven to be safe, and can significantly expedite the drug development process due to their already established safety profiles. In light of this, the present review offers a comprehensive overview of the various methods employed in drug repurposing, specifically focusing on the repurposing of drugs to treat cancer. We describe the antitumor properties of candidate drugs, and discuss in detail how they target both the hallmarks of cancer in tumor cells and the surrounding tumor microenvironment. In addition, we examine the innovative strategy of integrating drug repurposing with nanotechnology to enhance topical drug delivery. We also emphasize the critical role that repurposed drugs can play when used as part of a combination therapy regimen. To conclude, we outline the challenges associated with repurposing drugs and consider the future prospects of these repurposed drugs transitioning into clinical application.

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Targeting piRNA‐137463 Inhibits Tumor Progression and Boosts Sensitivity to Immune Checkpoint Blockade via De Novo Cholesterol Biosynthesis in Lung Adenocarcinoma

Zhan,

Tian,

Fan

et al. 2024

Advanced Science

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The important role of PIWI‐interacting RNAs (piRNAs) in tumors has garnered increasing attention. However, research on their role in lung adenocarcinoma (LUAD) remains limited. Elevated levels of piRNA‐137463 have been linked to poor prognosis in LUAD patients. Inhibition of piRNA‐137463 curbed the proliferation, migration, and invasion of LUAD cells, enhanced T cell cytotoxicity through increased IFN‐γ secretion, disrupted cholesterol metabolism, and reduced intracellular cholesterol, lipid raft content, and PD‐L1 expression in LUAD cells. Bioinformatic prediction identified a potential interaction between piRNA‐137463 and lncRNA LOC100128494. Inhibiting piRNA‐137463 increased the stability and expression of LOC100128494, which further modulated insulin‐induced gene 1 protein (INSIG1) levels via a competitive endogenous RNA network involving LOC100128494 and miR‐24‐3p. Notably, the effect of piRNA‐137463 in LUAD cells is dependent on the expression of LOC100128494 and INSIG1. Inhibiting the expression of piRNA‐137463 with AntagopiRNA‐137463 suppressed tumor growth and metastasis via LOC100128494 in nude mice and enhanced the response of LUAD to anti‐PD‐1 therapy in immune‐competent mice. In summary, this study elucidates the role of piRNA‐137463 in the reprogramming of cholesterol metabolism, which drives the progression of LUAD, thereby identifying a new target for the comprehensive clinical management of LUAD.

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Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications

Cited by 13 publications

References 165 publications

Residual OXPHOS is required to drive primary and metastatic lung tumours in an orthotopic breast cancer model

Residual OXPHOS is required to drive primary and metastatic lung tumours in an orthotopic breast cancer model

Drug repurposing for cancer therapy

Targeting piRNA‐137463 Inhibits Tumor Progression and Boosts Sensitivity to Immune Checkpoint Blockade via De Novo Cholesterol Biosynthesis in Lung Adenocarcinoma

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