Apigenin, Chrysin, and Luteolin Selectively Inhibit Chymotrypsin-Like and Trypsin-Like Proteasome Catalytic Activities in Tumor Cells

Abstract

The ubiquitin–proteasome pathway has an important role in regulating apoptosis and the cell cycle. The function of proteasomes is mediated by three main catalytic activities: (1) chymotrypsin-like (CT‐L), (2) trypsin-like (T‐L), and (3) peptidylglutamyl peptide hydrolyzing (PGPH). Recently, proteasome inhibitors have been revealed to have an antitumor effect, and have been used to treat cancers such as multiple myeloma. Previous studies have reported that some flavonoids can inhibit proteasome activity in tumor cells. To further investigate the proteasome-inhibitory mechanism of flavonoids, we examined the effects of the plant flavonoids apigenin, chrysin, and luteolin on the three individual catalytic activities in various cancer cell lines. Using fluorogenic substrates specific for proteasome catalytic subunits, we demonstrated the subunit specificity of each flavonoid. Addition of apigenin, chrysin and luteolin inhibited CT‐L and T‐L catalytic activities in a dose-dependent manner, whereas their effect on PGPH catalytic activity was weak. Our study suggested that these flavonoids have a specific role in inhibition of CT‐L and T‐L proteasome catalytic activities.

flavonoids - proteasomes - inhibitors

References

• 1 Ciechanover A. The ubiquitin-proteasome pathway: on protein death and cell life.  EMBO J. 1998;  17 7151-7160
• 2 Li B, Dou Q P. Bax degradation by the ubiquitin-proteasome-dependent pathway: involvement in tumor survival and progression.  Proc Natl Acad Sci USA. 2000;  97 3850-3855
• 3 Myung J, Kim K B, Crews C M. The ubiquitin-proteasome pathway and proteasome inhibitors.  Med Res Rev. 2001;  21 245-273
• 4 Naujokat C, Hoffman S. Role and function of the 26S proteasome in proliferation and apoptosis.  Lab Invest. 2002;  82 956-980
• 5 Groll M, Heinemeyer W, Jager S, Ullrich T, Bochtler M, Wolf D H, Huber R. The catalytic sites of 20S proteasome and their role in subunit maturation: a mutational and crystallographic study.  Proc Natl Acad Sci USA. 1999;  96 10976-10983
• 6 Ciechanover A, Orian A, Schwartz A L. Ubiquitin-mediated proteolysis; biological reglation via destruction.  Bioessays. 2000;  22 442-451
• 7 Crawford L J, Walker B, Ovaa H, Chauhan D, Anderson K C, Morris T C, Irvine A F. Comparative selectivity and specificity of the proteasome inhibitors bzlllcocho, ps-341, and Mg-132.  Cancer Res. 2006;  66 6379-6386
• 8 Kazi A, Daniel K G, Smith D M, Kumar N B, Dou Q P. Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein.  Biochem Pharmacol. 2003;  66 965-976
• 9 Nam S, Smith D M, Dou Q P. Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo.  J Biol Chem. 2001;  276 13322-13330
• 10 Ross J A, Kasum C M. Dietary flavonoids: bioavailability, metabolic effects, and safety.  Annu Rev Nutr. 2002;  22 19-34
• 11 Feng X, Zhang L, Zhu H. Comparative anticancer and antioxidant activities of different ingredients of Ginkgo biloba extract (ECB761).  Planta Med. 2009;  75 792-796
• 12 Seelinger G, Merfort I, Schempp C M. Anti-oxidant, anti-inflammadtory and anti-allergic activities of luteolin.  Planta Med. 2008;  14 1667-1677
• 13 Neuhouser M L. Dietary flavonoids and cancer risk: evidence from human population studies.  Nutr Cancer. 2004;  50 1-7
• 14 Chen D, Chen M S, Cui Q C, Yang H, Dou Q P. Structure-proteasome-inhibitory activity relationships of dietary flavonoids in human cancer cells.  Frontiers Biosci. 2007;  12 1935-1945
• 15 Chen D, Daniel K G, Chen M S, Kuhn D J, Landis-Piwowar K R, Dou Q P. Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells.  Biochem Pharmacol. 2005;  69 1421-1432
• 16 Landis-Piwowar K R, Milacic V, Chen D, Yang H, Zhao Y, Chan T H, Yan B, Dou Q P. The proteasome as a potential target for novel anticancer drugs and chemosensitizers.  Drug Resist Updat. 2006;  9 263-273
• 17 Kane R C, Brose P F, Frarell A T, Pazdur R. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy.  Oncology. 2003;  8 508-513
• 18 Richardson P G, Barlogie B, Berenson J, Singhai S, Jagannath S, Irwin D, Rajkumar S V, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski R Z, Kuter D, Limentani S A, Lee S, Hideshima T, Esseltine D L, Kauffman M, Adams J, Schenkein D P, Anderson K C. A phase 2 study of bortezomib in relapsed, refractory myloma.  N Eng J Med. 2003;  348 2609-2617