Abstract
The D40 gene encodes a kinetochore protein that plays an essential role in kinetochore formation during mitosis. Short inhibitory RNA against D40, D40 siRNA, has been shown to deplete the D40 protein in the human cancer cell line HeLa, which harbors wild-type p53, and this activity was followed by the significant inhibition of cell growth and induction of apoptotic cell death. The p53-null cancer cell line, PC-3M-luc, is also sensitive to the significant growth inhibition and cell death induced by D40 siRNA. The growth of PC-3M-luc tumors transplanted into nude mice was inhibited by the systemic administration of D40 siRNA and the atelocollagen complex. Furthermore, D40 siRNA significantly inhibited growth and induced apoptotic cell death in a cell line with a gain-of-function (GOF) mutation in p53, MDA-MB231-luc, and also inhibited the growth of tumors transplanted into mice when administered as a D40 siRNA/atelocollagen complex. These results indicated that D40 siRNA induced apoptotic cell death in human cancer cell lines, and inhibited their growth in vitro and in vivo regardless of p53 status. Therefore, D40 siRNA is a potential candidate anti-cancer reagent.
Highlights
We previously described the cloning of the human gene D40 on chromosome 151, and we characterized D40 as a member of the cancer/testis gene family that is predominantly expressed in the testis and widely expressed in various cultured human cancer cell lines and primary tumors of different origins[2,3]
To examine the apoptotic pathway caused by D40 short inhibitory RNA (siRNA), we examined whether caspase 3/7 was activated in D40 siRNA-transfected cells compared with control siRNA-transfected cells
We demonstrated that D40 siRNA, a D40-specific short inhibitory RNA, markedly inhibited the growth of human cancer cell lines both in vitro and in vivo by inducing apoptosis in a p53 status-independent manner
Summary
We previously described the cloning of the human gene D40 on chromosome 151, and we characterized D40 as a member of the cancer/testis gene family that is predominantly expressed in the testis and widely expressed in various cultured human cancer cell lines and primary tumors of different origins[2,3]. Knl-1/Blinkin binds to Mis[12] and Ndc[80] complexes, which comprise the KMN network, and to several other proteins including tubulin, the spindle assembly checkpoint (SAC) proteins Bub[1] and BubR1, and Protein Phosphatase 1. By binding to these proteins, Knl-1/Blinkin plays critical roles in kinetochore formation, connecting chromosomes and spindles and regulating SAC6–11. Recent studies have shown that wild-type p53 increases the sensitivity of tumor cells to molecular targeted drugs, and p53 mutation conferred resistance to these drugs[20,21,22,23]. We propose that D40 siRNA may be a potential candidate for cancer therapy
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