Therapeutic effects of statins against lung adenocarcinoma via p53 mutant-mediated apoptosis

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Abstract

The p53 gene is an important tumour suppressor gene. Mutant p53 genes account for about half of all lung cancer cases. There is increasing evidence for the anti-tumour effects of statins via inhibition of the mevalonate pathway. We retrospectively investigated the correlation between statin use and lung cancer prognosis using the Taiwanese National Health Insurance Research Database, mainly focusing on early-stage lung cancer. This study reports the protective effects of statin use in early-stage lung cancer patients regardless of chemotherapy. Statin treatments reduced the 5-year mortality (odds ratio, 0.43; P < 0.001) in this population-based study. Significantly higher levels of cellular apoptosis, inhibited cell growth, and regulated lipid raft content were observed in mutant p53 lung cancer cells treated with simvastatin. Further, simvastatin increased the caspase-dependent apoptotic pathway, promotes mutant p53 protein degradation, and decreased motile activity in lung cancer cells with p53 missense mutations. These data suggest that statin use in selected lung cancer patients may have clinical benefits.

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Annual Report to the Nation on the Status of Cancer, 1975–2014, Featuring Survival

Ahmedin Jemal, Elizabeth Ward, Christopher J Johnson … (2017)

Abstract Background: The American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate to provide annual updates on cancer occurrence and trends in the United States. This Annual Report highlights survival rates. Methods: Data were from the CDC- and NCI-funded population-based cancer registry programs and compiled by NAACCR. Trends in age-standardized incidence and death rates for all cancers combined and for the leading cancer types by sex were estimated by joinpoint analysis and expressed as annual percent change. We used relative survival ratios and adjusted relative risk of death after a diagnosis of cancer (hazard ratios [HRs]) using Cox regression model to examine changes or differences in survival over time and by sociodemographic factors. Results: Overall cancer death rates from 2010 to 2014 decreased by 1.8% (95% confidence interval [CI] = –1.8 to –1.8) per year in men, by 1.4% (95% CI = –1.4 to –1.3) per year in women, and by 1.6% (95% CI = –2.0 to –1.3) per year in children. Death rates decreased for 11 of the 16 most common cancer types in men and for 13 of the 18 most common cancer types in women, including lung, colorectal, female breast, and prostate, whereas death rates increased for liver (men and women), pancreas (men), brain (men), and uterine cancers. In contrast, overall incidence rates from 2009 to 2013 decreased by 2.3% (95% CI = –3.1 to –1.4) per year in men but stabilized in women. For several but not all cancer types, survival statistically significantly improved over time for both early and late-stage diseases. Between 1975 and 1977, and 2006 and 2012, for example, five-year relative survival for distant-stage disease statistically significantly increased from 18.7% (95% CI = 16.9% to 20.6%) to 33.6% (95% CI = 32.2% to 35.0%) for female breast cancer but not for liver cancer (from 1.1%, 95% CI = 0.3% to 2.9%, to 2.3%, 95% CI = 1.6% to 3.2%). Survival varied by race/ethnicity and state. For example, the adjusted relative risk of death for all cancers combined was 33% (HR = 1.33, 95% CI = 1.32 to 1.34) higher in non-Hispanic blacks and 51% (HR = 1.51, 95% CI = 1.46 to 1.56) higher in non-Hispanic American Indian/Alaska Native compared with non-Hispanic whites. Conclusions: Cancer death rates continue to decrease in the United States. However, progress in reducing death rates and improving survival is limited for several cancer types, underscoring the need for intensified efforts to discover new strategies for prevention, early detection, and treatment and to apply proven preventive measures broadly and equitably.

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Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins.

Ruben Ramirez, Shelley Sheridan, Luc Girard … (2004)

By expressing two genes (hTERT and Cdk4), we have developed a method to reproducibly generate continuously replicating human bronchial epithelial cell (HBEC) lines that provide a novel resource to study the molecular pathogenesis of lung cancer and the differentiation of bronchial epithelial cells. Twelve human bronchial epithelial biopsy specimens obtained from persons with and without lung cancer were placed into short-term culture and serially transfected with retroviral constructs containing cyclin-dependent kinase (Cdk) 4 and human telomerase reverse transcriptase (hTERT), resulting in continuously growing cultures. The order of introduction of Cdk4 and hTERT did not appear to be important; however, transfection of either gene alone did not result in immortalization. Although they could be cloned, the immortalized bronchial cells did not form colonies in soft agar or tumors in nude mice. The immortalized HBECs have epithelial morphology; express epithelial markers cytokeratins 7, 14, 17, and 19, the stem cell marker p63, and high levels of p16(INK4a); and have an intact p53 checkpoint pathway. Cytogenetic analysis and array comparative genomic hybridization profiling show immortalized HBECs to have duplication of parts of chromosomes 5 and 20. Microarray gene expression profiling demonstrates that the Cdk4/hTERT-immortalized bronchial cell lines clustered together and with nonimmortalized bronchial cells, distinct from lung cancer cell lines. We also immortalized several parental cultures with viral oncoproteins human papilloma virus type 16 E6/E7 with and without hTERT, and these cells exhibited loss of the p53 checkpoint and significantly different gene expression profiles compared with Cdk4/hTERT-immortalized HBECs. These HBEC lines are a valuable new tool for studying of the pathogenesis of lung cancer.

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Statins and cancer prevention.

Marie-France Demierre, Peter Higgins, Stephen B. Gruber … (2005)

Randomized controlled trials for preventing cardiovascular disease indicated that statins had provocative and unexpected benefits for reducing colorectal cancer and melanoma. These findings have led to the intensive study of statins in cancer prevention, including recent, large population-based studies showing statin-associated reductions in overall, colorectal and prostate cancer. Understanding the complex cellular effects (for example, on angiogenesis and inflammation) and the underlying molecular mechanisms of statins (for example, 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase-dependent processes that involve geranylgeranylation of Rho proteins, and HMG-CoA-independent processes that involve lymphocyte-function-associated antigen 1) will advance the development of molecularly targeted agents for preventing cancer. This understanding might also help the development of drugs for other ageing-related diseases with interrelated molecular pathways.

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Author and article information

Contributors

Yuh-Pyng Sher: ypsher@mail.cmu.edu.tw

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 31 December 2019

Publication date PMC-release: 31 December 2019

Publication date Collection: 2019

Volume: 9

Electronic Location Identifier: 20403

Affiliations

[1 ]ISNI 0000 0001 0083 6092, GRID grid.254145.3, Graduate Institute of Biomedical Sciences, , China Medical University, ; Taichung, 404 Taiwan

[2 ]ISNI 0000 0001 0083 6092, GRID grid.254145.3, Chinese Medicine Research Center, , China Medical University, ; Taichung, 404 Taiwan

[3 ]ISNI 0000 0001 0083 6092, GRID grid.254145.3, Research Center for Chinese Herbal Medicine, , China Medical University, ; Taichung, 404 Taiwan

[4 ]ISNI 0000 0004 0572 9415, GRID grid.411508.9, Center for Molecular Medicine, , China Medical University Hospital, ; Taichung, 404 Taiwan

[5 ]ISNI 0000 0004 0573 0731, GRID grid.410764.0, Division of Hematology/Medical Oncology, Department of Medicine, , Taichung Veterans General Hospital, ; Taichung, 407 Taiwan

[6 ]ISNI 0000 0004 0573 0731, GRID grid.410764.0, Department of Medical Research, , Taichung Veterans General Hospital, ; Taichung, 407 Taiwan

[7 ]ISNI 0000 0004 0573 0483, GRID grid.415755.7, Department of Radiation Therapy and Oncology, , Shin Kong Wu Ho-Su Memorial Hospital, ; Taipei, 111 Taiwan

Article

Publisher ID: 56532

DOI: 10.1038/s41598-019-56532-6

PMC ID: 6938497

PubMed ID: 31892709

SO-VID: 1d92d4e2-6952-424d-a426-c75cf439c483

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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 15 January 2019

Date accepted : 11 December 2019

Funding

Funded by: FundRef https://doi.org/10.13039/501100010101, Taichung Veterans General Hospital (TCVGH);

Award ID: TCVGH-1073701B

Award Recipient : Cheng-Wei Chou

Funded by: FundRef https://doi.org/10.13039/501100004737, National Health Research Institutes (NHRI);

Award ID: NHRI-EX107-10706BI

Award ID: NHRI-EX108-10706BI

Award Recipient : Yuh-Pyng Sher

Funded by: FundRef https://doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan);

Award ID: MOST 108-2314-B-039-054-MY3

Award Recipient : Yuh-Pyng Sher

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ScienceOpen disciplines: Uncategorized

Keywords: targeted therapies,non-small-cell lung cancer

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ScienceOpen disciplines: Uncategorized

Keywords: targeted therapies, non-small-cell lung cancer

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Therapeutic effects of statins against lung adenocarcinoma via p53 mutant-mediated apoptosis

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Abstract

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Inflamed lung in vitro co-culture models

Most cited references 28

Annual Report to the Nation on the Status of Cancer, 1975–2014, Featuring Survival

Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins.

Statins and cancer prevention.

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Cited by 30

Most referenced authors 723