Identification of Siah-interacting protein as a potential regulator of apoptosis and curcumin resistance.
The mechanism underlying curcumin (diferuloylmethane) resistance is still largely unknown. Here we employed proteomic approach to identify the Siah-interacting protein (SIP) as a candidate for detailed study, because the spot intensity of SIP on a two-dimensional gel displayed 70-90% reduction in curcumin-sensitive cells, but remained unchanged in curcumin-resistant sublines, after curcumin treatment. Both gain- and loss-of-function studies revealed that SIP promoted curcumin-induced apoptosis. Moreover, SIP underwent phosphorylation and nuclear translocation in curcumin-sensitive but not resistant cells, upon curcumin exposure. The nuclear translocation of SIP was remarkably impaired when a putative nuclear localization sequence (NLS, amino acid (aa) 143-159) was deleted or the serine 141 was mutated into alanine, whereas truncation of the N-terminal region (aa 1-43) obviously increased the nuclear import of SIP. In accordance with their nuclear localization, N-terminal truncation significantly enhanced the proapoptotic effect of SIP, whereas NLS deletion or Ser141Ala mutation attenuated the apoptosis-promoting activity of both wild-type- and N-terminal truncated-SIP. These data suggest that SIP plays a role in apoptosis and curcumin resistance, and the function of SIP may be regulated by different motifs, such as the NLS, N-terminal region and serine 141. Our findings provide new insights into the biological significance of SIP and the mechanisms of drug resistance.
Luo
J
J
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.
Yang
J
J
Yu
B-Y
BY
Liu
W
W
Li
M
M
Zhuang
S-M
SM
D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D010766:Phosphorylation; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000970:Antineoplastic Agents; C491778:CACYBP protein, human; D002135:Calcium-Binding Proteins; D003474:Curcumin; D013755:Tetradecanoylphorbol Acetate