Simvastatin inhibits oral squamous cell carcinoma by targeting TMEM16A Ca2+-activated chloride channel

Wang, Hechen; Wang, Tianyu; Zhang, Zeying; Fan, Yu; Zhang, Lan; Gao, Kuan; Luo, Shuya; Xiao, Qinghuan; Sun, Changfu

doi:10.1007/s00432-021-03575-w

Cited by 9 publications

(4 citation statements)

References 63 publications

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“…The calcium-activated chloride channel TMEM16A, previously ANO1, is upregulated in diverse cancers [47] and commonly overexpressed in HNSCC, which is associated with poor outcomes [48,49], establishing it as a therapeutic target. Along with binding to EGFR that may impact HNC proliferation, survival and expression of PD-L1 and thus immune evasion [47,50], TMEM16A has been implicated in resistance to conventional therapy and EGFR-targeted agents.…”

Section: Cholesterol's Influence On Cancer Cell Proliferation Surviva...mentioning

confidence: 99%

“…TMEM16A upregulation can also suppress apoptosis and promote cisplatin resistance [51]. Simvastatin impairs TMEM16A channel function-potentially due to cholesterol depletion, though mevalonate-independent mechanisms may be involvedand reduces OSCC cell proliferation in a TMEM16A-dependent manner [49], suggesting statins as an alternative to TMEM16A inhibitors.…”

Section: Cholesterol's Influence On Cancer Cell Proliferation Surviva...mentioning

confidence: 99%

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Statins in Cancer Prevention and Therapy

Ricco

Kron

2023

Cancers

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Statins, a class of HMG-CoA reductase inhibitors best known for their cholesterol-reducing and cardiovascular protective activity, have also demonstrated promise in cancer prevention and treatment. This review focuses on their potential applications in head and neck cancer (HNC), a common malignancy for which established treatment often fails despite incurring debilitating adverse effects. Preclinical and clinical studies have suggested that statins may enhance HNC sensitivity to radiation and other conventional therapies while protecting normal tissue, but the underlying mechanisms remain poorly defined, likely involving both cholesterol-dependent and -independent effects on diverse cancer-related pathways. This review brings together recent discoveries concerning the anticancer activity of statins relevant to HNC, highlighting their anti-inflammatory activity and impacts on DNA-damage response. We also explore molecular targets and mechanisms and discuss the potential to integrate statins into conventional HNC treatment regimens to improve patient outcomes.

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Section: Cholesterol's Influence On Cancer Cell Proliferation Surviva...mentioning

confidence: 99%

Section: Cholesterol's Influence On Cancer Cell Proliferation Surviva...mentioning

confidence: 99%

Statins in Cancer Prevention and Therapy

Ricco

Kron

2023

Cancers

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“…The human Ether-à-go-go-related gene Kv11.1 (KCNH2 or hERG1) is expressed in several normal tissues, including cardiac tissue and smooth muscle, and in cancer cells it is regulated by several microRNAs relevant to tumor progression [53]. The overex-pression of the channel in different head and neck cancers is associated with cell growth, invasiveness, malignant transformation, and poor prognosis [75,109,124,174]; likewise, in HPV+ cervical adenocarcinoma, the inhibition of hERG1 alters cell cycle development [125]; meanwhile, in lung cancer, the gene silencing and application of channel blockers decreases cell proliferation (Table 2) [175].…”

Section: Voltage-gated Potassium Channelsmentioning

confidence: 99%

Ion Channels as Potential Tools for the Diagnosis, Prognosis, and Treatment of HPV-Associated Cancers

Chiliquinga,

Acosta,

Ogonaga-Borja

et al. 2023

Cells

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The human papilloma virus (HPV) group comprises approximately 200 genetic types that have a special affinity for epithelial tissues and can vary from producing benign symptoms to developing into complicated pathologies, such as cancer. The HPV replicative cycle affects various cellular and molecular processes, including DNA insertions and methylation and relevant pathways related to pRb and p53, as well as ion channel expression or function. Ion channels are responsible for the flow of ions across cell membranes and play very important roles in human physiology, including the regulation of ion homeostasis, electrical excitability, and cell signaling. However, when ion channel function or expression is altered, the channels can trigger a wide range of channelopathies, including cancer. In consequence, the up- or down-regulation of ion channels in cancer makes them attractive molecular markers for the diagnosis, prognosis, and treatment of the disease. Interestingly, the activity or expression of several ion channels is dysregulated in HPV-associated cancers. Here, we review the status of ion channels and their regulation in HPV-associated cancers and discuss the potential molecular mechanisms involved. Understanding the dynamics of ion channels in these cancers should help to improve early diagnosis, prognosis, and treatment in the benefit of HPV-associated cancer patients.

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“…Arctigenin and dehydroandrographolide also decreased the protein expression of TMEM16A in lung adenocarcinoma cells [ 92 ] and colorectal cancer cells [ 93 ], respectively. Moreover, Wang, et al found that simvastatin, a widely used cholesterol-lowing drug, suppressed TMEM16A channel activities, and inhibited cell proliferation in OSCC cells via TMEM16A in a mevalonate acid-independent way [ 94 ]. In addition, luteolin, a common dietary flavonoid, has various biological effects including anticancer activity against multiple types of human cancer cell lines [ 95 ].…”

Section: Introductionmentioning

confidence: 99%

TMEM16A as a potential treatment target for head and neck cancer

Okuyama

Yanamoto

2022

J Exp Clin Cancer Res

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Transmembrane protein 16A (TMEM16A) forms a plasma membrane-localized Ca2+-activated Cl- channel. Its gene has been mapped to an area on chromosome 11q13, which is amplified in head and neck squamous cell carcinoma (HNSCC). In HNSCC, TMEM16A overexpression is associated with not only high tumor grade, metastasis, low survival, and poor prognosis, but also deterioration of clinical outcomes following platinum-based chemotherapy. Recent study revealed the interaction between TMEM16A and transforming growth factor-β (TGF-β) has an indirect crosstalk in clarifying the mechanism of TMEM16A-induced epithelial-mesenchymal transition. Moreover, human papillomavirus (HPV) infection can modulate TMEM16A expression along with epidermal growth factor receptor (EGFR), whose phosphorylation has been reported as a potential co-biomarker of HPV-positive cancers. Considering that EGFR forms a functional complex with TMEM16A and is a co-biomarker of HPV, there may be crosstalk between TMEM16A expression and HPV-induced HNSCC. EGFR activation can induce programmed death ligand 1 (PD-L1) synthesis via activation of the nuclear factor kappa B pathway and JAK/STAT3 pathway. Here, we describe an interplay among EGFR, PD-L1, and TMEM16A. Combination therapy using TMEM16A and PD-L1 inhibitors may improve the survival rate of HNSCC patients, especially those resistant to anti-EGFR inhibitor treatment. To the best of our knowledge, this is the first review to propose a biological validation that combines immune checkpoint inhibition with TMEM16A inhibition.

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Simvastatin inhibits oral squamous cell carcinoma by targeting TMEM16A Ca2+-activated chloride channel

Cited by 9 publications

References 63 publications

Statins in Cancer Prevention and Therapy

Statins in Cancer Prevention and Therapy

Ion Channels as Potential Tools for the Diagnosis, Prognosis, and Treatment of HPV-Associated Cancers

TMEM16A as a potential treatment target for head and neck cancer

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