Title: Ergosterol peroxide activates Foxo3-mediated cell death signaling by inhibiting AKT and c-Myc in human hepatocellular carcinoma cells
Author(s): Xiangmin Li1,2,3,*, Qingping Wu1,*, Ming Bu4,*, Liming Hu4, William W. Du2,3, Chunwei Jiao1,5, Honghui Pan1, Mouna Sdiri2,3, Nan Wu2,3, Yizhen Xie1,5, Burton B. Yang2,3,6
Research Journal: Oncotarget, Volume 7, pages 33948-33959
Year of Publication: 2016
Article Link: https://doi.org/10.18632/oncotarget.8608
What is this research article about?
This research study follows up on previous findings, from this group of scientists, that oil extracted from Ganoderma spores is very powerful in causing cancer cell death – also causing death of cancer stem-like cells.
ⓘ Similar to normal stem cells in our body, there is a scientific theory that among all cancerous cells, a special group of cancer cells act as stem cells that reproduce themselves and contribute to cancer proliferation.
An important discovery is that ergosterol peroxide, within Ganoderma Lucidum oil, is a key bioactive compound that inhibits tumour growth by anti-angiogenesis or cytotoxicity. Researchers investigated how, ergosterol peroxide causes cancer cell death i.e. the molecular mechanisms that induces in cell death; this study focused on liver cancer cells.
ⓘ In non-scientific jargon, ergosterol peroxide stops cancer tumour growth by:
- Preventing tumours from generating their own blood supply – cutting off nutrients and oxygen
- Acting as a toxic substance that kills cancer cells
What are the main research findings?
Researchers reported that they observed the following biological functions of ergosterol peroxide on human hepatocellular carcinoma cells:
- Inhibited cell viability and induced cell death
- Inhibited cell cycle progression and colony growth
- Reduced cancer cell survival and migration
ⓘ "Hepatocellular" refers to liver cells.
These observed functions on cancer cells were attributed to ergosterol peroxide regulating several important gene expressions. E.g., decreased c-myc levels, increased levels of BAX and PUMA.
ⓘ c-myc is a gene associated with tumour growth.
ⓘ BAX and PUMA are genes that support cancer cell death.
Research Article Abstract
Sterols are the important active ingredients of fungal secondary metabolites to induce death of tumor cells. In our previous study, we found that ergosterol peroxide (5α, 8α-epidioxiergosta-6, 22-dien-3β-ol), purified from Ganoderma lucidum, induced human cancer cell death. Since the amount of purified ergosterol peroxide is not sufficient to perform in vivo experiments or apply clinically, we developed an approach to synthesize ergosterol peroxide chemically. After confirming the production of ergosterol peroxide, we examined the biological functions of the synthetic ergosterol peroxide. The results showed that ergosterol peroxide induced cell death and inhibited cell migration, cell cycle progression, and colony growth of human hepatocellular carcinoma cells. We further examined the mechanism associated with this effect and found that treatment with ergosterol peroxide increased the expression of Foxo3 mRNA and protein in HepG2 cells. The upstream signal proteins pAKT and c-Myc, which can inhibit Foxo3 functions, were clearly decreased in HepG2 cells treated with ergosterol peroxide. The levels of Puma and Bax, pro-apoptotic proteins, were effectively enhanced. Our results suggest that ergosterol peroxide stimulated Foxo3 activity by inhibiting pAKT and c-Myc and activating pro-apoptotic protein Puma and Bax to induce cancer cell death.
Hepatocellular carcinoma is one of the most common neoplasms worldwide, which frequently develops in the site of chronic hepatitis or cirrhosis. It would be helpful to prevent the development of hepatocellular carcinoma in the high-risk group of patients with chronic hepatitis or cirrhosis. Natural health products have attracted extensive attention in health promotion and disease treatment including cancer. In addition, natural product-based drug discovery is a major route leading to developing therapeutic drugs for various diseases including cancer. Medicinal mushrooms are a large group of natural product which are extensively used in health promotion and drug development. Ganoderma lucidum is the most known medicinal mushroom and is regarded as the folk medicine used for prevention and treatment of various human diseases, especially cancer. The other members of this family also possess anti-tumor activity.
2Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada
3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
4College of Life Science and Bioengineering, Beijing University of Technology, Pingleyuan, Chaoyang, Beijing, China
5Guangdong Yuewei Edible Fungi Technology Co. Ltd, Guangzhou, China
6 Institute of Medical Science, University of Toronto, Toronto, Canada
*These authors contributed equally to this work