Statin-induced metabolic reprogramming in head and neck cancer: a biomarker for targeting monocarboxylate transporters.
Authors
Mehibel, MOrtiz-Martinez, F
Voelxen, N
Boyers, A
Chadwick, A
Telfer, B
Mueller-Klieser, W
West, Catharine ML
Critchlow, S
Williams, Kaye J
Stratford, I
Affiliation
Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UKIssue Date
2018
Metadata
Show full item recordAbstract
Prognosis of HPV negative head and neck squamous cell carcinoma (HNSCC) patients remains poor despite surgical and medical advances and inadequacy of predictive and prognostic biomarkers in this type of cancer highlights one of the challenges to successful therapy. Statins, widely used for the treatment of hyperlipidaemia, have been shown to possess anti-tumour effects which were partly attributed to their ability to interfere with metabolic pathways essential in the survival of cancer cells. Here, we have investigated the effect of statins on the metabolic modulation of HNSCC cancers with a vision to predict a personalised anticancer therapy. Although, treatment of tumour-bearing mice with simvastatin did not affect tumour growth, pre-treatment for 2 weeks prior to tumour injection, inhibited tumour growth resulting in strongly increased survival. This was associated with increased expression of the monocarboxylate transporter 1 (MCT1) and a significant reduction in tumour lactate content, suggesting a possible reliance of these tumours on oxidative phosphorylation for survival. Since MCT1 is responsible for the uptake of mitochondrial fuels into the cells, we reasoned that inhibiting it would be beneficial. Interestingly, combination of simvastatin with AZD3965 (MCT1 inhibitor) led to further tumour growth delay as compared to monotherapies, without signs of toxicity. In clinical biopsies, prediagnostic statin therapy was associated with a significantly higher MCT1 expression and was not of prognostic value following conventional chemo-radiotherapy. These findings provide a rationale to investigate the clinical effectiveness of MCT1 inhibition in patients with HNSCC who have been taking lipophilic statins prior to diagnosis.Citation
Mehibel M, Ortiz-Martinez F, Voelxen N, Boyers A, Chadwick A, Telfer B, et al. Statin-induced metabolic reprogramming in head and neck cancer: a biomarker for targeting monocarboxylate transporters. Sci Rep. 2018 Nov 14;8(1):16804.Journal
Scientific ReportsDOI
10.1038/s41598-018-35103-1PubMed ID
30429503Additional Links
https://dx.doi.org/10.1111/bph.14542Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1038/s41598-018-35103-1
Scopus Count
Collections
Related articles
- Cellular Uptake of MCT1 Inhibitors AR-C155858 and AZD3965 and Their Effects on MCT-Mediated Transport of L-Lactate in Murine 4T1 Breast Tumor Cancer Cells.
- Authors: Guan X, Rodriguez-Cruz V, Morris ME
- Issue date: 2019 Jan 7
- Monocarboxylate transporter 1 blockade with AZD3965 inhibits lipid biosynthesis and increases tumour immune cell infiltration.
- Authors: Beloueche-Babari M, Casals Galobart T, Delgado-Goni T, Wantuch S, Parkes HG, Tandy D, Harker JA, Leach MO
- Issue date: 2020 Mar
- Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer.
- Authors: Polański R, Hodgkinson CL, Fusi A, Nonaka D, Priest L, Kelly P, Trapani F, Bishop PW, White A, Critchlow SE, Smith PD, Blackhall F, Dive C, Morrow CJ
- Issue date: 2014 Feb 15
- Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer.
- Authors: Curry JM, Tuluc M, Whitaker-Menezes D, Ames JA, Anantharaman A, Butera A, Leiby B, Cognetti DM, Sotgia F, Lisanti MP, Martinez-Outschoorn UE
- Issue date: 2013 May 1
- Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma.
- Authors: Noble RA, Bell N, Blair H, Sikka A, Thomas H, Phillips N, Nakjang S, Miwa S, Crossland R, Rand V, Televantou D, Long A, Keun HC, Bacon CM, Bomken S, Critchlow SE, Wedge SR
- Issue date: 2017 Jul