Abstract
Two-dimensional gel electrophoresis and liquid chromatography-tandem mass spectrometry were performed to investigate the influence of human nonmetastatic clone 23 type 1 (nm23-H1), a metastasis-associated gene on proteomic alterations in cancer cells of the uterine cervix. It was validated by RT-PCR and Western blot analysis. The expression of voltage-dependent anion channel 1 (VDAC1) was increased in nm23-H1 gene silenced SiHa or CaSki cervical cancer cells. The clinical implication was shown that cervical cancer tissues with positive VDAC1 immunoreactivity exhibited deep stromal invasion (>10 mm in depth) and large tumor size (> 4 cm in diameter). Cervical cancer patients with positive VDAC1 immunoreactivity displayed higher recurrence and poorer overall survival than those with negative VDAC1. Silencing of VDAC1 reduced cell proliferation and migratory ability. Mitochondrial membrane potential was decreased and reactive oxygen species generation was increased in the VDAC1 gene-silenced cervical cancer cells. Cell cycle progression and autophagy were not changed in VDAC1 silencing cells. The cytotoxicity of cisplatin was significantly enhanced by knockdown of cellular VDAC1 and the compounds that interfere with hexokinase binding to VDAC. Therapeutic strategies may be offered using VDAC1 as a target to reduce cell growth and migration, enhance the synergistic therapeutic efficacy of cisplatin and reduce cisplatin dose-limiting toxicity.
Highlights
Our previous experiment, using genechips, revealed that human nonmetastatic clone 23 type 1 has decreased the expression of voltage-dependent anion channel 1 (VDAC1) in cancer cells of the uterine cervix
After the nm23-H1 gene had been silenced by lentiviruses carrying shnm23-H1 #62, we identified and quantified some nm23-H1 associated proteins with high scores using 2D electrophoresis (Table 1)
We investigated the clinical implication of VDAC1 in cervical cancer and found that the immunoreactivity was significantly stronger in cervical cancer tissues than that in normal tissues (p
Summary
Our previous experiment, using genechips, revealed that human nonmetastatic clone 23 type 1 (nm23-H1) has decreased the expression of voltage-dependent anion channel 1 (VDAC1) in cancer cells of the uterine cervix. VDAC1 was hypothesized to be associated with the development and progression of cervical cancer. VDAC1 is mainly located at the outer mitochondrial membrane (OMM) and is the most abundant protein in OMM. It forms a channel for the entry and exit of metabolites across the OMM [2,3,4]. Because VDAC1 can bind with pro-apoptotic [5,6,7,8,9,10] or anti-apoptotic proteins [11,12,13,14], it may stimulate or inhibit the apoptosis, growth and survival of cervical cancer cells respectively. Mitochondrial membrane permeability may be controlled by the mitochondrial permeability pore (PTP) [15]
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