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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

RCC2 over-expression in tumor cells alters apoptosis and drug sensitivity by regulating Rac1 activation

Authors: Nan Wu, Dong Ren, Su Li, Wenli Ma, Shaoyan Hu, Yan Jin, Sheng Xiao

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

Small GTP binding protein Rac1 is a component of NADPH oxidases and is essential for superoxide-induced cell death. Rac1 is activated by guanine nucleotide exchange factors (GEFs), and this activation can be blocked by regulator of chromosome condensation 2 (RCC2), which binds the switch regions of Rac1 to prevent access from GEFs.

Methods

Three cancer cell lines with up- or down-regulation of RCC2 were used to evaluate cell proliferation, apoptosis, Rac1 signaling and sensitivity to a group of nine chemotherapeutic drugs. RCC2 expression in lung cancer and ovarian cancer were studied using immunochemistry stain of tumor tissue arrays.

Results

Forced RCC2 expression in tumor cells blocked spontaneous- or Staurosporine (STS)-induced apoptosis. In contrast, RCC2 knock down in these cells resulted in increased apoptosis to STS treatment. The protective activity of RCC2 on apoptosis was revoked by a constitutively activated Rac1, confirming a role of RCC2 in apoptosis by regulating Rac1. In an immunohistochemistry evaluation of tissue microarray, RCC2 was over-expressed in 88.3% of primary lung cancer and 65.2% of ovarian cancer as compared to non-neoplastic lung and ovarian tissues, respectively. Because chemotherapeutic drugs can kill tumor cells by activating Rac1/JNK pathway, we suspect that tumors with RCC2 overexpression would be more resistant to these drugs. Tumor cells with forced RCC2 expression indeed had significant difference in drug sensitivity compared to parental cells using a panel of common chemotherapeutic drugs.

Conclusions

RCC2 regulates apoptosis by blocking Rac1 signaling. RCC2 expression in tumor can be a useful marker for predicting chemotherapeutic response.
Literature
1.
Andreassen P, Palmer D, Wener M, Margolis R. Telophase disc: a new mammalian mitotic organelle that bisects telophase cells with a possible function in cytokinesis. J Cell Sci. 1991;99:523–34.PubMed
2.
Mollinari C, Reynaud C, Martineau-Thuillier S, et al. The mammalian passenger protein TD-60 is an RCC1 family member with an essential role in Prometaphase to metaphase progression. Dev Cell. 2003;5:295–307.CrossRefPubMed
3.
Williamson R, Cowell C, Hammond C, et al. Coronin-1C and RCC2 guide mesenchymal migration by trafficking Rac1 and controlling GEF exposure. J Cell Sci. 2014;127:4292–307.CrossRefPubMedPubMedCentral
4.
Humphries J, Byron A, Bass M, et al. Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6. Sci Signal. 2009;2(87):ra51.CrossRefPubMedPubMedCentral
5.
Sit S-T, Manser E. Rho GTPases and their role in organizing the actin cytoskeleton. Cell science at a glance. 2011;124:679–83.CrossRef
6.
Sundaresan M, ZX Y, Ferrans VJ, et al. Regulation of reactive-oxygen-species generation in fibroblasts by Rac1. The Biochemical Journal. 1996;318:379–82.CrossRefPubMedPubMedCentral
7.
Sulciner DJ, Irani K, ZX Y, et al. Rac1 regulates a cytokine-stimulated, redox-dependent pathway necessary for NF-kappaB activation. Mol Cell Biol. 1996;16(12):7115–21.CrossRefPubMedPubMedCentral
8.
Cheng G, Diebold B, Hughes Y, Lambeth J. Nox1-dependent reactive oxygen generation is regulated by Rac1. J Biol Chem. 2006;281:17718–26.CrossRefPubMed
9.
Kim Y, Morgan M, Choksi S, Liu Z. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol Cell. 2007;26:675–87.CrossRefPubMed
10.
11.
Hordijk PL. Regulation of NADPH Oxidases. Reviews. 2006;98:453–62.
12.
Kao Y-Y, Gianni D, Bohl B, et al. Identification of a conserved Rac-binding site on NADPH Oxidases supports a direct GTPase regulatory mechanism. J Biol Chem. 2008;283(19):12736–46.CrossRefPubMedPubMedCentral
13.
14.
Wang T-H, Chan Y-H, Chen C-W, et al. Oncogene - abstract of article: Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways. Oncogene. 2006;25:4857–66.CrossRefPubMed
15.
Subauste CM, Von Herrath M, Benard V, et al. Rho family proteins modulate rapid apoptosis induced by Cytotoxic T lymphocytes and Fas. J Biol Chem. 2000;275:9725–33.CrossRefPubMed
16.
Stacey S, Gudbjartsson D, Sulem P, et al. Common variants on 1p36 and 1q42 are associated with cutaneous basal cell carcinoma but not with melanoma or pigmentation traits. Nat Genet. 2008;40:1313–8.CrossRefPubMed
17.
18.
Matsuo M, Nakada C, Tsukamoto Y, et al. MiR-29c is downregulated in gastric carcinomas and regulates cell proliferation by targeting RCC2. Mol Cancer. 2013;12:15–24.CrossRefPubMedPubMedCentral
19.
Bruun J, Kolberg M, Ahlquist T, et al. Regulator of chromosome condensation 2 identifies high-risk patients within both major phenotypes of colorectal cancer. Clinical cancer research. 2015;21:3759–70.CrossRefPubMed
20.
Lorès P, Morin L, Luna R, Gacon G. Enhanced apoptosis in the thymus of transgenic mice expressing constitutively activated forms of human Rac2GTPase. Oncogene. 1997;15:601–5.CrossRefPubMed
21.
Eom Y, Yoo M, Woo C, et al. Implication of the small GTPase Rac1 in the apoptosis induced by UV in rat-2 fibroblasts. Biochem Biophys Res Commun. 2001;285:825–9.CrossRefPubMed
22.
Ito M, Adachi T, Pimentel DR, et al. Statins inhibit beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes via a Rac1-dependent mechanism. Circulation. 2004;110:412–8.CrossRefPubMed
23.
Kalra N, Kumar V. C-fos is a mediator of the c-myc-induced apoptotic signaling in serum-deprived Hepatoma cells via the p38 Mitogen-activated protein Kinase pathway. J Biol Chem. 2004;279:25313–9.CrossRefPubMed
24.
Kim S, Moon A. Capsaicin-induced apoptosis of H-ras-transformed human breast epithelial cells is Rac-dependent via ROS generation. Arch Pharm Res. 2004;27:845–9.CrossRefPubMed
25.
Jin S, Ray R, Johnson L. Rac1 mediates intestinal epithelial cell apoptosis via JNK. Am J Physiol Gastrointest Liver Physiol. 2006;291:1137–47.CrossRef
26.
27.
Lee S, Sim N, Clement M, et al. Dominant negative Rac1 attenuates paclitaxel-induced apoptosis in human melanoma cells through upregulation of heat shock protein 27: a functional proteomic analysis. Proteomics. 2007;7:4112–22.CrossRefPubMed
28.
Kanekura K, Hashimoto Y, Kita Y, et al. A Rac1/Phosphatidylinositol 3-Kinase/Akt3 anti-apoptotic pathway, triggered by AlsinLF, the product of the ALS2 gene, antagonizes cu/Zn-superoxide dismutase (SOD1) mutant-induced Motoneuronal cell death. J Biol Chem. 2005;280:4532–43.CrossRefPubMed
29.
Jeong H-G, Cho H-J, Chang I-Y, et al. Rac1 prevents cisplatin-induced apoptosis through down-regulation of p38 activation in NIH3T3 cells. FEBS Lett. 2002;518:129–34.CrossRefPubMed
30.
Murga C, Zohar M, Teramoto H, Gutkind J. Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-kappaB. Oncogene. 2002;21:207–16.CrossRefPubMed
31.
Zhang Z, Liang X, Gao L, et al. TIPE1 induces apoptosis by negatively regulating Rac1 activation in hepatocellular carcinoma cells. Oncogene. 2014;34:2566–74.CrossRefPubMed
32.
Deshpande S, Angkeow P, Huang J, et al. Rac1 inhibits TNF-alpha-induced endothelial cell apoptosis: dual regulation by reactive oxygen species. FASEB J. 2000;14:1705–14.CrossRefPubMed
33.
Sooman L, Ekman S, Andersson C, et al. Synergistic interactions between camptothecin and EGFR or RAC1 inhibitors and between imatinib and notch signaling or RAC1 inhibitors in glioblastoma cell lines. Cancer Chemother Pharmacol. 2013;72:329–40.CrossRefPubMed
34.
Johnson MA, Sharma M, Mok MT, et al. Stimulation of in vivo nuclear transport dynamics of actin and its co-factors IQGAP1 and Rac1 in response to DNA replication stress. Biochim Biophys Acta. 2013;1833(10):2334–47.CrossRefPubMed
35.
Michaelson D, Abidi W, Guardavaccaro D, et al. Rac1 accumulates in the nucleus during the G2 phase of the cell cycle and promotes cell division. J Cell Biol. 2008;181(3):485–96.CrossRefPubMedPubMedCentral
Metadata
Title
RCC2 over-expression in tumor cells alters apoptosis and drug sensitivity by regulating Rac1 activation
Authors
Nan Wu
Dong Ren
Su Li
Wenli Ma
Shaoyan Hu
Yan Jin
Sheng Xiao
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3908-y

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