Ursolic acid induces apoptosis and anoikis in colorectal carcinoma RKO cells

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Abstract

Background

Ursolic acid (UA) is an anti-cancer herbal compound. In the present study, we observed the effects of UA on anchorage-dependent and -independent growth of human colorectal cancer (CRC) RKO cells.

Methods

RKO cells were cultured in conventional and detached condition and treated with UA. Cell viability was evaluated by CCK-8 assay. Cell cycle was analyzed by flow cytometry. Apoptosis was identified by Hoechst 33258 staining and flow cytometry analysis. Activities of caspases were measured by commercial kits. Reactive oxygen species (ROS) was recognized by DCFH-DA fluorescent staining. Anoikis was identified by EthD-1 fluorescent staining and flow cytometry analysis. Expression and phosphorylation of proteins were analyzed by western blot.

Results

UA inhibited RKO cell viability in both a dose- and time-dependent manner. UA arrested the cell cycle at the G0/G1 phase, and induced caspase-dependent apoptosis. UA inhibited Bcl-2 expression and increased Bax expression. In addition, UA up-regulated the level of ROS that contributed to UA activated caspase-3, − 8 and − 9, and induced apoptosis. Furthermore, UA inhibited cell growth in a detached condition and induced anoikis in RKO cells that was accompanied by dampened phosphorylation of FAK, PI3K and AKT. UA also inhibited epithelial-mesenchymal transition (EMT) as indicated by the down-regulation of N-Cad expression and up-regulation of E-Cad expression.

Conclusions

UA induced caspase-dependent apoptosis, and FAK/PI3K/AKT singling and EMT related anoikis in RKO cells. UA was an effective anti-cancer compound against both anchorage-dependent and -independent growth of RKO cells.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12906-021-03232-2.

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Most cited references 24

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Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Ahmedin Jemal, Lindsey A Torre, Rebecca Siegel … (2018)

This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.

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Hallmarks of Cancer: The Next Generation

Douglas Hanahan, Robert A. Weinberg (2011)

The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

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Activation of apoptosis signalling pathways by reactive oxygen species.

Maureen Redza-Dutordoir, Diana Averill-Bates (2016)

Reactive oxygen species (ROS) are short-lived and highly reactive molecules. The generation of ROS in cells exists in equilibrium with a variety of antioxidant defences. At low to modest doses, ROS are considered to be essential for regulation of normal physiological functions involved in development such as cell cycle progression and proliferation, differentiation, migration and cell death. ROS also play an important role in the immune system, maintenance of the redox balance and have been implicated in activation of various cellular signalling pathways. Excess cellular levels of ROS cause damage to proteins, nucleic acids, lipids, membranes and organelles, which can lead to activation of cell death processes such as apoptosis. Apoptosis is a highly regulated process that is essential for the development and survival of multicellular organisms. These organisms often need to discard cells that are superfluous or potentially harmful, having accumulated mutations or become infected by pathogens. Apoptosis features a characteristic set of morphological and biochemical features whereby cells undergo a cascade of self-destruction. Thus, proper regulation of apoptosis is essential for maintaining normal cellular homeostasis. ROS play a central role in cell signalling as well as in regulation of the main pathways of apoptosis mediated by mitochondria, death receptors and the endoplasmic reticulum (ER). This review focuses on current understanding of the role of ROS in each of these three main pathways of apoptosis. The role of ROS in the complex interplay and crosstalk between these different signalling pathways remains to be further unravelled during the coming years.

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Author and article information

Contributors

Bing Hu:

ORCID: http://orcid.org/0000-0003-0810-6670

beearhu@hotmail.com , beearhu@shutcm.edu.cn

Journal

Journal ID (nlm-ta): BMC Complement Med Ther

Journal ID (iso-abbrev): BMC Complement Med Ther

Title: BMC Complementary Medicine and Therapies

Publisher: BioMed Central (London )

ISSN (Electronic): 2662-7671

Publication date (Electronic): 6 February 2021

Publication date PMC-release: 6 February 2021

Publication date Collection: 2021

Volume: 21

Electronic Location Identifier: 52

Affiliations

[1 ]GRID grid.412540.6, ISNI 0000 0001 2372 7462, Institute of Traditional Chinese Medicine in Oncology, Longhua Hospital, , Shanghai University of Traditional Chinese Medicine, ; Shanghai, 200032 People’s Republic of China

[2 ]GRID grid.412540.6, ISNI 0000 0001 2372 7462, Department of Oncology, Longhua Hospital, , Shanghai University of Traditional Chinese Medicine, ; Shanghai, 200032 People’s Republic of China

[3 ]GRID grid.412540.6, ISNI 0000 0001 2372 7462, Shanghai University of Traditional Chinese Medicine, ; Shanghai, 201203 People’s Republic of China

[4 ]GRID grid.412540.6, ISNI 0000 0001 2372 7462, Department of Science & Technology, Longhua Hospital, , Shanghai University of Traditional Chinese Medicine, ; Shanghai, 200032 People’s Republic of China

Author information

Bing Hu http://orcid.org/0000-0003-0810-6670

Article

Publisher ID: 3232

DOI: 10.1186/s12906-021-03232-2

PMC ID: 7866452

PubMed ID: 33549076

SO-VID: 73771bc7-93ac-42b7-9231-53c48e2b37b4

License:

Open AccessThis 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 : 26 October 2020

Date accepted : 28 January 2021

Funding

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

Award ID: 82074352

Award Recipient : Bing Hu

Funded by: Natural Science Foundation of Shanghai Municipality

Award ID: 20ZR1458700

Award Recipient : Bing Hu

Funded by: Natural Science Foundation of Longhua Hospital

Award ID: 2018YM03

Award Recipient : Jia-Lu Zheng

Funded by: Program from Science & Technology Commission of Shanghai Municipality

Award ID: 19401933400

Award Recipient : Bing Hu

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Keywords: ursolic acid,colorectal cancer,apoptosis,caspases,reactive oxygen species,anoikis,fak,pi3k,akt,epithelial-mesenchymal transition

Data availability:

Keywords: ursolic acid, colorectal cancer, apoptosis, caspases, reactive oxygen species, anoikis, fak, pi3k, akt, epithelial-mesenchymal transition

Ursolic acid induces apoptosis and anoikis in colorectal carcinoma RKO cells

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Abstract

Background

Methods

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Conclusions

Supplementary Information

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Gamma Delta T cells

Most cited references 24

Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Hallmarks of Cancer: The Next Generation

Activation of apoptosis signalling pathways by reactive oxygen species.

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