Targeting the Vav3 oncogene enhances docetaxel-induced apoptosis through the inhibition of androgen receptor phosphorylation in LNCaP prostate cancer cells under chronic hypoxia

Molecular Cancer

Research

Keiko Matsuura¹  Masatsugu Moriyama¹  Hiromitsu Mimata²  Fuminori Sato²  Ryuta Sato²  Takeo Nomura²  Toru Inoue²  Kenichi Hirai²  Mutsushi Yamasaki² 

[1] Department of Molecular Pathology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, 879-5593, Yufu, Oita, Japan;Department of Urology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, 879-5593, Yufu, Oita, Japan;

关键词: Vav3;    Docetaxel;    Androgen receptor;    Prostate cancer;    Chronic hypoxia;   

DOI  :  10.1186/1476-4598-12-27

 received in 2012-09-11, accepted in 2013-04-04,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundThe Vav family of Rho/Rac guanosine nucleotide exchange factors comprises three members in mammalian cells. Vav3 enhances androgen receptor (AR) activity during progression to androgen independence in prostate cancer. We examined Vav3 small interfering RNA (siRNA) effects on cell proliferation and apoptosis in docetaxel-treated LNCaP cells under chronic hypoxia (LNCaPH).MethodsWe examined individual and combined effects of Vav3 siRNA (si-Vav3) and docetaxel on cell growth and apoptosis under chronic hypoxia by cell proliferation, flow cytometric, DNA fragmentation, and immunoblot analyses. To clarify the molecular basis of si-Vav3- and docetaxel-induced apoptosis, we analyzed alterations in phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulate kinase (ERK), c-jun N-terminal kinase (JNK), and AR pathways using kinase inhibitors in LNCaPH cells. The effects of si-Vav3/atelocollagen complex alone or in combination with docetaxel were assessed on xenografts in nude mice by tumor growth delay.ResultsVav3 overexpression was observed in LNCaPH compared with the expression under normoxia. Interrupting Vav3 signaling using siRNA enhanced docetaxel-induced cell growth suppression compared with that induced by docetaxel alone by inhibition of Akt and ERK phosphorylation, resulting in AR phosphorylation inhibition. In addition to increased B-cell lymphoma 2 (Bcl-2) phosphorylation through JNK signaling in response to docetaxel, si-Vav3 enhanced docetaxel-induced apoptosis, as characterized by the accumulation of sub-G1 phase cells and DNA fragmentation, through Bcl-xL/Bcl-2-associated death promoter (Bad) dephosphorylation, resulting in increased caspase-9, caspase-3, and cleaved poly(ADP-ribose) polymerase activation. Xenograft tumor growth was slightly inhibited by si-Vav3/atelocollagen complex injection and combined use of si-Vav3/atelocollagen complex and docetaxel produced a greater effect than docetaxel alone.ConclusionsInterrupting Vav3 signaling enhances docetaxel-induced apoptosis in LNCaP cells under chronic hypoxia by inhibiting the PI3K/Akt, ERK, and AR signaling pathways. Therapy targeting Vav3 in combination with docetaxel may have practical implications for managing castration-resistant prostate cancer.

【 授权许可】

CC BY   
© Nomura et al.; licensee BioMed Central Ltd. 2013