Hispolon from Phellinus linteus has antiproliferative effects via MDM2-recruited ERK1/2 activity in breast and bladder cancer cells.
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.
Lu
Te-Ling
TL
School of Pharmacy, China Medical University, Taichung, Taiwan. lutl@mail.cmu.edu.tw
Huang
Guan-Jhong
GJ
Lu
Te-Jung
TJ
Wu
Jin-Bin
JB
Wu
Chieh-Hsi
CH
Yang
Tung-Chuan
TC
Iizuka
Akira
A
Chen
Yuh-Fung
YF
D000363:Agaricales / Q000737:chemistry*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D053179:Caspase 7 / Q000096:biosynthesis; D002396:Catechols / Q000302:isolation & purification / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D004790:Enzyme Induction; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D007202:Indicators and Reagents; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D002396:Catechols; D007202:Indicators and Reagents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016159:Tumor Suppressor Protein p53; C103442:hispolon; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D011065:Poly(ADP-ribose) Polymerases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053179:Caspase 7