Modulation of proteasome activity by curcumin and didemethylcurcumin

Abstract

Modulation of proteasome function by pharmacological interventions and molecular biology tools is an active area of research in cancer biology and neurodegenerative diseases. Curcumin (diferuloylmethane) is a naturally occurring polyphenol that affects multiple signaling pathways. Curcumin shows anti-inflammatory, antioxidant, anti-angiogenic, or anti-apoptotic properties. Recent research suggests that the therapeutic efficacy of curcumin may be due to its activity as a potent inhibitor of the proteasome. Using in vitro cell culture and molecular docking methods, here we show that both curcumin and its synthetic polyphenolic derivative (didemethylcurcumin, CUIII) modulated proteasome activity in a biphasic manner. Curcumin and CUIII increased proteasome activity at nanomolar concentrations, but inhibited proteasome activity at micromolar concentrations. Curcumin was more effective than CUIII in increasing relative proteasome activity at nanomolar concentrations. Also, curcumin was more effective than CUIII in inhibiting relative proteasome activity at micromolar concentrations. Docking simulations of curcumin and didemethylcurcumin binding to the 20S proteasome catalytic subunit estimated K_d values of 0.0054 µM and 1.3167 µM, respectively. These values correlate well with the results of the effectiveness of modulation by curcumin compared to CUIII. The small size of CUIII allows it to dock to the narrow cavity of the active site, but the binding interaction is not strong compared to curcumin. These results indicate that curcumin and its didemethyl derivative can be used to modulate proteasome activity and suggest that curcumin and its didemethyl derivative may be useful in treating two different disease classes: neurodegeneration and cancer.

Communicated by Ramaswamy H. Sarma

Keywords:

• Curcumin
• didemethylcurcumin
• proteasome
• molecular docking
• neurodegeneration
• cancer

Disclosure statement

Authors declare no conflicts of interest and their respective Institutes have no other agreements and financial interest in this work.

Additional information

Funding

The research was partly supported by the Intramural Research Program of The Rockefeller Neuroscience Institute (formerly, Blanchette Rockefeller Neurosciences Institute) at West Virginia University, Morgantown, WV (T.K.K.) and funding from National Institutes of Health Grant 1R01 AA022414 to J.D.