Browse > Article
http://dx.doi.org/10.7314/APJCP.2015.16.9.3805

Arsenic Trioxide Inhibits Cell Growth and Invasion via Down-Regulation of Skp2 in Pancreatic Cancer Cells  

Gao, Jian-Kun (Department of Basic Medical Sciences, Sichuan College of Traditional Chinese Medicine)
Wang, Li-Xia (Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University)
Long, Bo (Infectious Diseases Department, Mianyang 404 Hospital)
Ye, Xian-Tao (Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University)
Su, Jing-Na (Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University)
Yin, Xu-Yuan (Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University)
Zhou, Xiu-Xia (Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University)
Wang, Zhi-Wei (Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.16, no.9, 2015 , pp. 3805-3810 More about this Journal
Abstract
Arsenic trioxide (ATO) has been found to exert anti-cancer activity in various human malignancies. However, the molecular mechanisms by which ATO inhibits tumorigenesis are not fully elucidated. In the current study, we explored the molecular basis of ATO-mediated tumor growth inhibition in pancreatic cancer cells. We used multiple approaches such as MTT assay, wound healing assay, Transwell invasion assay, annexin V-FITC, cell cycle analysis, RT-PCR and Western blotting to achieve our goal. We found that ATO treatment effectively caused cell growth inhibition, suppressed clonogenic potential and induced G2-M cell cycle arrest and apoptosis in pancreatic cancer cells. Moreover, we observed a significant down-regulation of Skp2 after treatment with ATO. Furthermore, we revealed that ATO regulated Skp2 downstream genes such as FOXO1 and p53. These findings demonstrate that inhibition of Skp2 could be a novel strategy for the treatment of pancreatic cancer by ATO.
Keywords
Arsenic trioxide; Skp2; cell growth; apoptosis; pancreatic cancer;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Chan CH, Morrow JK, Li CF, et al (2013). Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression. Cell, 154, 556-68.   DOI
2 Chan CH, Morrow JK, Zhang S, et al (2014). Skp2: a dream target in the coming age of cancer therapy. Cell cycle, 13, 679-80.   DOI
3 Chander H, Halpern M, Resnick-Silverman L, et al (2010). Skp2B attenuates p53 function by inhibiting prohibitin. EMBO Reports, 11, 220-5.   DOI
4 Chen Q, Xie W, Kuhn DJ, et al (2008). Targeting the p27 E3 ligase SCF (Skp2) results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy. Blood, 111, 4690-9.   DOI
5 de The H, Chen Z (2010). Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nature Reviews. Cancer, 10, 775-83.   DOI
6 Einama T, Kagata Y, Tsuda H, et al (2006). High-level Skp2 expression in pancreatic ductal adenocarcinoma: correlation with the extent of lymph node metastasis, higher histological grade, and poorer patient outcome. Pancreas, 32, 376-81.   DOI
7 Elmahi AY, Niu C, Li W, et al (2013). Effects of arsenic trioxide alone and in combination with bortezomib in multiple myeloma RPMI 8266 cells. Asian Pac J Cancer Prev, 14, 6469-73.   DOI
8 Fan GH, Wang ZM, Yang X, et al (2014). Resveratrol inhibits oesophageal adenocarcinoma cell proliferation via AMP-activated protein kinase signaling. Asian Pac J Cancer Prev, 15, 677-82.   DOI   ScienceOn
9 Fujita T, Liu W, Doihara H, et al (2008). Dissection of the APCCdh1-Skp2 cascade in breast cancer. Clin Cancer Res, 14, 1966-75.   DOI
10 Han JB, Sang F, Chang JJ, et al (2013). Arsenic trioxide inhibits viability of pancreatic cancer stem cells in culture and in a xenograft model via binding to SHH-Gli. OncoTargets Therapy, 6, 1129-38.
11 Huang H, Regan KM, Wang F, et al (2005a). Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. P Natl Acad Sci USA, 102, 1649-54.   DOI
12 Huang H, Regan KM, Wang F, et al (2005b). Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc Natl Acad Sci USA, 102, 1649-54.   DOI
13 Huang HC, Lin CL, Lin JK (2011). 1,2,3,4,6-penta-O-galloyl-beta-D-glucose, quercetin, curcumin and lycopene induce cell-cycle arrest in MDA-MB-231 and BT474 cells through downregulation of Skp2 protein. J Agric Food Chem, 59, 6765-75.   DOI   ScienceOn
14 Huang HC, Way TD, Lin CL, et al (2008). EGCG stabilizes p27kip1 in E2-stimulated MCF-7 cells through down-regulation of the Skp2 protein. Endocrinology, 149, 5972-83.   DOI
15 Inuzuka H, Gao D, Finley LW, et al (2012). Acetylation-dependent regulation of Skp2 function. Cell, 150, 179-93.   DOI
16 Li X, Ding X, Adrian TE (2003). Arsenic trioxide induces apoptosis in pancreatic cancer cells via changes in cell cycle, caspase activation, and GADD expression. Pancreas, 27, 174-9.   DOI
17 Kamura T, Hara T, Kotoshiba S, et al (2003). Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation. Proc Natl Acad Sci USA, 100, 10231-6.   DOI
18 Kindler HL, Aklilu M, Nattam S, et al (2008). Arsenic trioxide in patients with adenocarcinoma of the pancreas refractory to gemcitabine: a phase II trial of the University of Chicago Phase II Consortium. Am J Clin Oncol, 31, 553-6.   DOI
19 Li X, Ding X, Adrian TE (2002). Arsenic trioxide inhibits proliferation and induces apoptosis in pancreatic cancer cells. Anticancer Res, 22, 2205-13.
20 Li X, Ding X, Adrian TE (2004). Arsenic trioxide causes redistribution of cell cycle, caspase activation, and GADD expression in human colonic, breast, and pancreatic cancer cells. Cancer investigation, 22, 389-400.   DOI
21 Lu W, Liu S, Li B, et al (2015). SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination. Oncotarget, 6, 771-88.   DOI
22 Mi JQ, Li JM, Shen ZX, et al (2012). How to manage acute promyelocytic leukemia. Leukemia, 26, 1743-51.   DOI
23 Michl P, Gress TM (2013). Current concepts and novel targets in advanced pancreatic cancer. Gut, 62, 317-26.   DOI
24 Radke S, Pirkmaier A, Germain D (2005). Differential expression of the F-box proteins Skp2 and Skp2B in breast cancer. Oncogene, 24, 3448-58.   DOI
25 Siegel RL, Miller KD, Jemal A (2015). Cancer statistics, 2015. Ca Cancer J Clin, 65, 5-29.   DOI
26 Rico-Bautista E, Yang CC, Lu L, et al (2010). Chemical genetics approach to restoring p27Kip1 reveals novel compounds with antiproliferative activity in prostate cancer cells. BMC Biol 8, 153.   DOI
27 Roy S, Kaur M, Agarwal C, et al (2007). p21 and p27 induction by silibinin is essential for its cell cycle arrest effect in prostate carcinoma cells. Mol Cancer Ther, 6, 2696-707.   DOI
28 Schuler S, Diersch S, Hamacher R, et al (2011). SKP2 confers resistance of pancreatic cancer cells towards TRAIL-induced apoptosis. Int J Oncol, 38, 219-25.
29 Subbarayan PR, Ardalan B (2014). In the war against solid tumors arsenic trioxide need partners. J Gastrointest Cancer, 45, 363-71.   DOI
30 Torre LA, Bray F, Siegel RL, et al (2015). Global cancer statistics, 2012. Ca Cancer J Clin, 65, 87-108.   DOI
31 Tsvetkov LM, Yeh KH, Lee SJ, et al (1999). p27 (Kip1) ubiquitination and degradation is regulated by the SCF (Skp2) complex through phosphorylated Thr187 in p27. Current Biol, 9, 661-4.
32 Wang G, Chan CH, Gao Y, et al (2012a). Novel roles of Skp2 E3 ligase in cellular senescence, cancer progression, and metastasis. Chinese J Cancer, 31, 169-77.   DOI
33 Wang J, Huang Y, Guan Z, et al (2014a). E3-ligase Skp2 predicts poor prognosis and maintains cancer stem cell pool in nasopharyngeal carcinoma. Oncotarget, 5, 5591-601.   DOI
34 Wang W, Adachi M, Zhang R, et al (2009). A novel combination therapy with arsenic trioxide and parthenolide against pancreatic cancer cells. Pancreas, 38, 114-23.   DOI
35 Wu L, Grigoryan AV, Li Y, et al (2012). Specific small molecule inhibitors of Skp2-mediated p27 degradation. Chem Biol, 19, 1515-24.   DOI
36 Wang Z, Gao D, Fukushima H, et al (2012b). Skp2: a novel potential therapeutic target for prostate cancer. Biochim Biophys Acta, 1825, 11-7.
37 Wang Z, Liu P, Inuzuka H, et al (2014b). Roles of F-box proteins in cancer. Nature Reviews Cancer, 14, 233-47.   DOI
38 Wang ZY, Chen Z (2008). Acute promyelocytic leukemia: from highly fatal to highly curable. Blood, 111, 2505-15.   DOI
39 Yang ES, Burnstein KL (2003). Vitamin D inhibits G1 to S progression in LNCaP prostate cancer cells through p27Kip1 stabilization and Cdk2 mislocalization to the cytoplasm. J Biol Chem, 278, 46862-8.   DOI
40 Yu ZK, Gervais JL, Zhang H (1998). Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21 (CIP1/WAF1) and cyclin D proteins. Proc Natl Acad Sci USA, 95, 11324-9.   DOI
41 Zhou J (2012). Arsenic trioxide: an ancient drug revived. Chinese Med J, 125, 3556-60.