Cancer preventive isothiocyanates induce selective degradation of cellular alpha- and beta-tubulins by proteasomes.
Although it is conceivable that cancer preventive isothiocyanates (ITCs), a family of compounds in cruciferous vegetables, induce cell cycle arrest and apoptosis through a mechanism involving oxidative stress, our study shows that binding to cellular proteins correlates with their potencies of apoptosis induction. More recently, we showed that ITCs bind selectively to tubulins. The differential binding affinities toward tubulin among benzyl isothiocyanate, phenethyl isothiocyanate, and sulforaphane correlate well with their potencies of inducing tubulin conformation changes, microtubule depolymerization, and eventual cell cycle arrest and apoptosis in human lung cancer A549 cells. These results support that tubulin binding by ITCs is an early event for cell growth inhibition. Here we demonstrate that ITCs can selectively induce degradation of both alpha- and beta-tubulins in a variety of human cancer cell lines in a dose- and time-dependent manner. The onset of degradation, a rapid and irreversible process, is initiated by tubulin aggregation, and the degradation is proteasome-dependent. Results indicate that the degradation is triggered by ITC binding to tubulin and is irrelevant to oxidative stress. This is the first report that tubulin, a stable and abundant cytoskeleton protein required for cell cycle progression, can be selectively degraded by a small molecule.
Mi
Lixin
L
From the Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, D. C. 20057. Electronic address: lm293@georgetown.edu.
Gan
Nanqin
N
From the Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, D. C. 20057.
Cheema
Amrita
A
From the Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, D. C. 20057.
Dakshanamurthy
Sivanesan
S
From the Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, D. C. 20057.
Wang
Xiantao
X
From the Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, D. C. 20057.
Yang
David C H
DCH
Department of Chemistry, Georgetown University, Washington, D. C. 20057.
Chung
Fung-Lung
FL
From the Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, D. C. 20057. Electronic address: flc6@georgetown.edu.