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Hispolon from Phellinus linteus has antiproliferative effects via MDM2-recruited ERK1/2 activity in breast and
Te-Ling Lu1, Guan-Jhong Huang, Te-Jung Lu
1School of Pharmacy, China Medical University, Taichung, Taiwan. lutl@mail.cmu.edu.tw
Abstract:
The MDM2 proto-oncogene is overexpressed in many human tumors. Although MDM2 inhibits tumor-suppressor function of p53, there exists a p53-independent role for MDM2 in tumorigenesis. Therefore, downregulation of MDM2 has been considered an attractive therapeutic strategy. Hispolon extracted from Phellinus species was found to induce epidermoid and gastric cancer cell apoptosis. However, the mechanisms are not fully understood. Herein, we report our findings that hispolon inhibited breast and bladder cancer cell growth, regardless of p53 status. Furthermore, p21(WAF1), a cyclin-dependent kinase inhibitor, was elevated in hispolon-treated cells. MDM2, a negative regulator of p21(WAF1), was ubiquitinated and degraded after hispolon treatment. We also found that activated ERK1/2 (extracellular signal-regulated kinase1/2) was recruited to MDM2 and involved in mediating MDM2 ubiquitination. Based on this finding, we investigated whether the sensitivity of cells to hispolon was related to ERK1/2 activity. The results indicated that cells with higher ERK1/2 activity were more sensitive to hispolon. In addition, hispolon-induced caspase-7 cleavage was inhibited by the ERK1/2 inhibitor, U0126. In conclusion, hispolon ubiquitinates and downregulates MDM2 via MDM2-recruited activated ERK1/2. Therefore, hispolon may be a potential anti-tumor agent in breast and bladder cancers.
Insights
Hispolon, a natural compound, degrades MDM2 (a cancer-promoting protein) by recruiting activated ERK1/2 (extracellular signal-regulated kinase1/2). This action inhibits breast and bladder cancer cell growth, suggesting hispolon as a potential anti-tumor agent.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- MDM2 proto-oncogene overexpression is common in human tumors.
- MDM2 inhibits p53 tumor suppressor function, but also has p53-independent roles in tumorigenesis.
- Targeting MDM2 for downregulation is a promising therapeutic strategy.
Purpose of the Study:
- To investigate the anti-cancer mechanisms of hispolon, a compound from Phellinus species.
- To determine if hispolon affects cancer cell growth irrespective of p53 status.
- To elucidate the molecular pathways involved in hispolon's anti-cancer effects.
Main Methods:
- Assessed hispolon's effect on breast and bladder cancer cell growth.
- Measured p21(WAF1) levels in hispolon-treated cells.
- Investigated MDM2 ubiquitination and degradation following hispolon treatment.
- Examined the role of activated ERK1/2 (extracellular signal-regulated kinase1/2) in MDM2 ubiquitination and hispolon sensitivity.
Main Results:
- Hispolon inhibited breast and bladder cancer cell growth, independent of p53 status.
- Hispolon treatment led to increased p21(WAF1) levels.
- Hispolon induced MDM2 ubiquitination and degradation.
- Activated ERK1/2 was recruited to MDM2, mediating its ubiquitination, and higher ERK1/2 activity correlated with increased sensitivity to hispolon.
Conclusions:
- Hispolon ubiquitinates and downregulates MDM2 through ERK1/2 recruitment.
- Hispolon demonstrates potential as an anti-tumor agent for breast and bladder cancers.
- The p53-independent mechanism highlights hispolon's broad applicability.
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