Senescence, an inherent tumor suppressive mechanism, is a critical determinant for chemotherapy. In the present study, we show that the monocarboxylate transporter 2 (MCT2) protein was tumor-selectively expressed in human colorectal malignancies and knockdown of MCT2 induces mitochondrial dysfunction, cell-cycle arrest, and senescence without additional cellular stress in colorectal cancer cell lines. Moreover, the reactive oxygen species (ROS) scavenger, N-acetylcysteine, blocked MCT2 knockdown-induced growth arrest and cellular senescence, indicating a pivotal role of ROS in this pathway. Dramatic induction of mitochondrial superoxide generation and decrease in ATP production was observed, indicating that mitochondrial dysfunction is the major mechanism underlying MCT2 knockdown-induced ROS generation. Senescenceassociated DNA damage was also evident from the increase in promyelocytic leukemia bodies, gH2AX foci, and SAHF. Conversely, overexpression of MCT2 prevented doxorubicin-induced ROS accumulation (P ¼ 0.0002) and cell growth inhibition (P ¼ 0.001). MCT2 knockdown suppressed KRAS mutant colorectal tumor growth in vivo. In addition, MCT2 knockdown and cytostatic drug combination further enhanced the antitumor effect. These findings support the use of MCT2 as a promising target for inhibition of colorectal cancer. Mol Cancer Ther; 11(11); 2342-51. Ó2012 AACR.
The constitutive activation of NF-kB is a major event leading to the initiation, development, and progression of cancer. Recently, we showed that the size of preestablished tumors was reduced after the depletion of Kir2.2, an inwardly rectifying potassium channel. To determine the precise mechanism of action of Kir2.2 in the control of tumor growth, we searched for interacting proteins. Notably, NF-kB p65/RelA was identified as a binding partner of Kir2.2 in a yeast two-hybrid analysis. Further analyses revealed that Kir2.2 directly interacted with RelA in vitro and coimmunoprecipitated with RelA from cell lysates. Kir2.2 increased RelA phosphorylation at S536 and facilitated its translocation from the cytoplasm to the nucleus, thereby activating the transcription factor and increasing the expression level of NF-kB targets, including cyclin D1, matrix metalloproteinase (MMP)9, and VEGF. Kir2.2 was overexpressed in human cancer and the expression level was correlated with increased colony formation and tumor growth in mouse tumor models. On the basis of these findings, we propose an unconventional role for Kir2.2 as a constitutive RelA-activating protein, which is likely to contribute to tumor progression in vivo. Cancer Res; 73(3); 1056-62. Ó2012 AACR.
a b s t r a c tPrevious studies have shown that testisin promotes malignant transformation in cancer cells. To define the mechanism of testisin-induced carcinogenesis, we performed yeast two-hybrid analysis and identified maspin, a tumor suppressor protein, as a testisin-interacting molecule. The direct interaction and cytoplasmic co-localization of testisin with maspin was confirmed by immunoprecipitation and confocal analysis, respectively. In cervical cancer cells, maspin modulated cell death and invasion; however, these effects were inhibited by testisin in parallel experiments. Of interest, the doxorubicin resistance was dramatically reduced by testisin knockdown (P = 0.016). Moreover, testisin was found to be over-expressed in cervical cancer samples as compared to matched normal cervical tissues. Thus, we postulate that testisin may promote carcinogenesis by inhibiting tumor suppressor activity of maspin.
Abstract. Ku70, a DNA repair protein, was recently identified as a critical anti-apoptotic protein that inhibits Bax translocation to mitochondria. The dissociation of Bax from Ku70 is essential for the apoptotic activity of Bax. Here, we show that maspin, a tumor suppressor protein frequently lost in cancer, regulates this process. Maspin increased cell death in a Ku70 acetylation-dependent manner. Maspin inhibited histone deacetylase 1 (HDAC1) and thus increased the acetylation of Ku70 and the dissociation of Bax from Ku70, which led to the induction of apoptosis. These results reveal maspin as a Ku70-interacting molecule and provide the basis for a new endogenous acetylation-based control mechanism that reduces Ku70-mediated sequestration of Bax from mitochondria.
The purpose of this study was to investigate the effects of a Action Learning(AL) program in terms of problem solving, communication skills, emotional creativity and innovation behaviors. Design for this was a nonequivalent control group quasi-experimental study. The participants were C-hospital staff nurses in G city (Experimental group=29, Control group=30). The AL program was composed of fourteen sessions in eight weeks. Data were collected and the program was conducted from May. 26 to July. 18, 2008. Data were analyzed with χ²-test, Fisher's exact test, t-test and ANCOVA, and utilized the SPSS win 20.0 program. There were significant increases in problem solving skills, communication skills and emotional creativity in the experimental group compared to the control group. Considering the above results, AL program has proven to be an effective educational program for improving the problem solving, communication skills and emotional creativity of nurses.
The purpose of this study was to describe outcome indicators of nursing education including critical thinking, professionalism, leadership, and communication and to evaluate differences among nursing programs and academic years. A descriptive research design was employed. A total of 454 students from four year baccalaureate (BS) nursing programs and two three-year associate degree (AD) programs consented to complete self-administered questionnaires. The variables were critical thinking, professionalism, leadership and communication. Descriptive statistics, χ2-test, t-tests, ANOVA, and the Tukey test were utilized for the data analysis. All the mean scores of the variables were above average for the test instruments utilized. Among the BS students, those in the upper classes tended to attain higher scores, but this tendency was not identified in AD students. There were significant differences between BS students and AD students for the mean scores of leadership and communication. These findings suggested the need for further research to define properties of nursing educational outcomes, and to develop standardized instruments for research replication and verification.
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