Mitochondrial impairment and downregulation of Drp1 phosphorylation underlie the antiproliferative and proapoptotic effects of alantolactone on oral squamous cell carcinoma cells

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Abstract

Background

Oral squamous cell carcinoma (OSCC) is one of the most prevalent and fatal oral cancers. Mitochondria-targeting therapies represent promising strategies against various cancers, but their applications in treating OSCC are limited. Alantolactone (ALT) possesses anticancer properties and also regulates mitochondrial events. In this study, we explored the effects of ALT on OSCC and the related mechanisms.

Methods

The OSCC cells were treated with varying concentrations and duration of ALT and N-Acetyl- l-cysteine (NAC). The cell viability and colony formation were assessed. The apoptotic rate was evaluated by flow cytometry with Annexin V-FITC/PI double staining. We used DCFH-DA and flow cytometry to detect reactive oxygen species (ROS) production and DAF-FM DA to investigate reactive nitrogen species (RNS) level. Mitochondrial function was reflected by mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP levels. KEGG enrichment analyses determined the mitochondrial-related hub genes involved in OSCC progression. Dynamin-related protein 1 (Drp1) overexpression plasmids were further transfected into the cells to analyze the role of Drp1 in OSCC progression. Immunohistochemistry staining and western blot verified the expression of the protein.

Results

ALT exerted anti-proliferative and pro-apoptosis effects on OSCC cells. Mechanistically, ALT elicited cell injury by promoting ROS production, mitochondrial membrane depolarization, and ATP depletion, which were reversed by NAC. Bioinformatics analysis showed that Drp1 played a crucial role in OSCC progression. OSCC patients with low Drp1 expression had a higher survival rate. The OSCC cancer tissues presented higher phosphorylated-Drp1 and Drp1 levels than the normal tissues. The results further showed that ALT suppressed Drp1 phosphorylation in OSCC cells. Moreover, Drp1 overexpression abolished the reduced Drp1 phosphorylation by ALT and promoted the cell viability of ALT-treated cells. Drp1 overexpression also reversed the mitochondrial dysfunction induced by ALT, with decreased ROS production, and increased mitochondrial membrane potential and ATP level.

Conclusions

ALT inhibited proliferation and promoted apoptosis of oral squamous cell carcinoma cells via impairment of mitochondrial homeostasis and regulation of Drp1. The results provide a solid basis for ALT as a therapeutic candidate for treating OSCC, with Drp1 being a novel therapeutic target in treating OSCC.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-023-04188-2.

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Most cited references 49

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Daniel E. Johnson, Barbara Burtness, C. René Leemans … (2020)

Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative or HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent premalignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporated additional information relevant to HPV-positive disease. The treatment approach is generally multimodal, consisting of surgery followed by chemotherapy plus radiation (chemoradiation or CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where co-morbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least toxic therapies.

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ROS signalling in the biology of cancer.

Jennifer N. Moloney, Thomas G. Cotter (2017)

Increased reactive oxygen species (ROS) production has been detected in various cancers and has been shown to have several roles, for example, they can activate pro-tumourigenic signalling, enhance cell survival and proliferation, and drive DNA damage and genetic instability. Counterintuitively ROS can also promote anti-tumourigenic signalling, initiating oxidative stress-induced tumour cell death. Tumour cells express elevated levels of antioxidant proteins to detoxify elevated ROS levels, establish a redox balance, while maintaining pro-tumourigenic signalling and resistance to apoptosis. Tumour cells have an altered redox balance to that of their normal counterparts and this identifies ROS manipulation as a potential target for cancer therapies. This review discusses the generation and sources of ROS within tumour cells, the regulation of ROS by antioxidant defence systems, as well as the effect of elevated ROS production on their signalling targets in cancer. It also provides an insight into how pro- and anti-tumourigenic ROS signalling pathways could be manipulated in the treatment of cancer.

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Author and article information

Contributors

Peng Zou: zoupeng123@163.com

Zhennan Deng: dengzhennan@wmu.edu.cn

Xiaoyu Sun:

ORCID: http://orcid.org/0000-0003-4494-6749

sunxyu198912@163.com

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 18 May 2023

Publication date PMC-release: 18 May 2023

Publication date Collection: 2023

Volume: 21

Electronic Location Identifier: 328

Affiliations

[1 ]GRID grid.268099.c, ISNI 0000 0001 0348 3990, School and Hospital of Stomatology, Institute of Stomatology, , Wenzhou Medical University, ; Wenzhou, China

[2 ]GRID grid.268099.c, ISNI 0000 0001 0348 3990, School of Pharmaceutical Sciences, , Wenzhou Medical University, ; Wenzhou, China

[3 ]GRID grid.268099.c, ISNI 0000 0001 0348 3990, Department of Prosthodontics, School and Hospital of Stomatology, , Wenzhou Medical University, ; Wenzhou, China

[4 ]GRID grid.268099.c, ISNI 0000 0001 0348 3990, The First Affiliated Hospital of Wenzhou Medical University, , Wenzhou Medical University, ; Wenzhou, China

[5 ]GRID grid.12380.38, ISNI 0000 0004 1754 9227, Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioral and Movement Sciences, , Vrije Universiteit Amsterdam (VU), Amsterdam Movement Sciences (AMS), ; Amsterdam, The Netherlands

[6 ]GRID grid.268099.c, ISNI 0000 0001 0348 3990, Department of Periodontics, School and Hospital of Stomatology, , Wenzhou Medical University, ; Wenzhou, China

[7 ]GRID grid.268099.c, ISNI 0000 0001 0348 3990, School and Hospital of Stomatology, , Wenzhou Medical University, ; Wenzhou, China

[8 ]GRID grid.12380.38, ISNI 0000 0004 1754 9227, Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC and Academic Center for Dentistry Amsterdam (ACTA), , Vrije Universiteit Amsterdam (VU), Amsterdam Movement Science (AMS), ; Amsterdam, The Netherlands

[9 ]GRID grid.7177.6, ISNI 0000000084992262, Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam (ACTA), , University of Amsterdam (UvA) and Vrije Universiteit Amsterdam (VU), ; Amsterdam, The Netherlands

Author information

Xiaoyu Sun http://orcid.org/0000-0003-4494-6749

Article

Publisher ID: 4188

DOI: 10.1186/s12967-023-04188-2

PMC ID: 10193726

PubMed ID: 37198593

SO-VID: 0525d1b8-ea3c-45c9-8bf3-88d1eb685574

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 14 February 2023

Date accepted : 8 May 2023

Funding

Funded by: the Wenzhou Science and Technology Bureau

Award ID: Y2020116

Award ID: Y20190102

Award Recipient : Xiaoyu Sun

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81901015

Award ID: 82104175

Award Recipient : Yixin Mao Xiaoyu Sun

Funded by: Zhejiang Provincial Natural Science Foundation of China

Award ID: LY21H140003

Award Recipient : Xiaoyu Sun

Funded by: Foundation for a new star of the medical industry in Zhejiang Province

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: oral squamous cell carcinoma (oscc),alantolactone (alt),reactive oxygen species (ros),mitochondrial impairment,dynamin-related protein 1 (drp1)

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ScienceOpen disciplines: Medicine

Keywords: oral squamous cell carcinoma (oscc), alantolactone (alt), reactive oxygen species (ros), mitochondrial impairment, dynamin-related protein 1 (drp1)

Mitochondrial impairment and downregulation of Drp1 phosphorylation underlie the antiproliferative and proapoptotic effects of alantolactone on oral squamous cell carcinoma cells

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Abstract

Background

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Supplementary Information

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Most cited references 49

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Head and neck squamous cell carcinoma

ROS signalling in the biology of cancer.

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