Involvement of regulations of nucleophosmin and nucleoporins in gambogic acid-induced apoptosis in Jurkat cells.
Gambogic acid, the main active compound of gamboge resin of Garcinia hanburryi, has recently exhibited marked antitumour potency on solid tumours of various derivations. We demonstrate here that gambogic acid also present powerful antileukaemic potency through both growth arrest and apoptosis induction in Jurkat cells, which was accompanied by typical apoptotic morphological changes and sharp decreased expression of Bcl-xL and Bcl-2. Furthermore, nucleophosmin, recently demonstrated to be mutated and aberrantly localized in the cytoplasm of leukaemia blasts in a high proportion of patients with acute myeloid leukaemia, was over-expressed in Jurkat cells. As the sole site of nucleocytoplasmic communication, the protein components of nuclear pore complex, such as NUP98, NUP88, NUP214 complex, were also deregulated in Jurkat cells. Especially, NUP98 was found to distribute mainly at the cell membrane, while NUP88 and NUP214 situated not just at the nuclear envelope, but also in the cytoplasm. However, in vitro treatment with gambogic acid resulted in significantly reduced expression of nucleophosmin and all three nucleoporins in a dose-dependent manner. Moreover, most of NUP88 and NUP214 nucleoporins were relocated to the nuclear rim in the gambogic acid-treated cells. These results suggest that the fact that nucleophosmin and some nucleoporins might act as new targets of gambogic acid, correlates well with the sensitivity to gambogic acid, as well as the rate of apoptosis induced by gambogic acid. Mechanisms that regulate nucleocytoplasmic transport of proteins may provide novel opportunities for drug development.
Shu
Wenxiu
W
Department of Haematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Chen
Yan
Y
Li
Rui
R
Wu
Qing
Q
Cui
Guohui
G
Ke
Wenjuan
W
Chen
Zi
Z
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D019169:Jurkat Cells; D028861:Nuclear Pore Complex Proteins / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D000090243:Nucleophosmin; D044004:Xanthones / Q000494:pharmacology*
D000970:Antineoplastic Agents; C000716967:NPM1 protein, human; C085914:NUP214 protein, human; C104835:NUP88 protein, human; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; C465451:Nup98 protein, human; D044004:Xanthones; D000090243:Nucleophosmin; C052659:gambogic acid