Journal of Experimental & Clinical Cancer Research | |
The expression and role of protein kinase C (PKC) epsilon in clear cell renal cell carcinoma | |
Shaopeng Qiu3  Junxing Chen3  Chengqiang Mo3  Jincheng Pan3  Jintao Zhuang3  Zhu Wang1  Xiaopeng Mao3  Shengjie Guo2  Xiubo Li4  Kaiyuan Cao1  Bin Huang3  | |
[1] Research Center for Clinical Laboratory Standard, Zhongshan Medical School, Sun Yat-sen University, Guangzhou (510080), China;Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou (510060), China;Department of Urology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou (510080), China;Pulmonary disease institute, Guangzhou Chest Hospital Pulmonary Disease Institute, Guangzhou (510095), China | |
关键词: Clear cell; Renal cell carcinoma; Protein kinase C epsilon; | |
Others : 827282 DOI : 10.1186/1756-9966-30-88 |
|
received in 2011-08-16, accepted in 2011-09-28, 发布年份 2011 | |
【 摘 要 】
Protein kinase C epsilon (PKCε), an oncogene overexpressed in several human cancers, is involved in cell proliferation, migration, invasion, and survival. However, its roles in clear cell renal cell carcinoma (RCC) are unclear. This study aimed to investigate the functions of PKCε in RCC, especially in clear cell RCC, to determine the possibility of using it as a therapeutic target. By immunohistochemistry, we found that the expression of PKCε was up-regulated in RCCs and was associated with tumor Fuhrman grade and T stage in clear cell RCCs. Clone formation, wound healing, and Borden assays showed that down-regulating PKCε by RNA interference resulted in inhibition of the growth, migration, and invasion of clear cell RCC cell line 769P and, more importantly, sensitized cells to chemotherapeutic drugs as indicated by enhanced activity of caspase-3 in PKCε siRNA-transfected cells. These results indicate that the overexpression of PKCε is associated with an aggressive phenotype of clear cell RCC and may be a potential therapeutic target for this disease.
【 授权许可】
2011 Huang et al; licensee BioMed Central Ltd.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
20140713123343474.pdf | 1110KB | download | |
Figure 5. | 47KB | Image | download |
Figure 4. | 43KB | Image | download |
Figure 3. | 67KB | Image | download |
Figure 2. | 32KB | Image | download |
Figure 1. | 147KB | Image | download |
【 图 表 】
Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
【 参考文献 】
- [1]Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010, 60:277-300.
- [2]Klatte T, Pantuck AJ, Kleid MD, Belldegrun AS: Understanding the natural biology of kidney cancer: implications for targeted cancer therapy. Rev Urol 2007, 9:47-56.
- [3]Finley DS, Pantuck AJ, Belldegrun AS: Tumor biology and prognostic factors in renal cell carcinoma. Oncologist 2011, 16:4-13.
- [4]Jaken S: Protein kinase C isozymes and substrates. Curr Opin Cell Biol 8(1996):168-173.
- [5]Newton AC: Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem J 2003, 370:361-371.
- [6]Parker PJ, Parkinson SJ: AGC protein kinase phosphorylation and protein kinase C. Biochem Soc Trans 2001, 29:860-863.
- [7]Griner EM, Kazanietz MG: Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer 2007, 7:281-294.
- [8]Gutcher I, Webb PR, Anderson NG: The isoform-specific regulation of apoptosis by protein kinase C. Cell Mol Life Sci 2003, 60:1061-1070.
- [9]Gorin MA, Pan Q: Protein kinase Cε: an oncogene and emerging tumor biomarker. Mol Cancer 2009, 8:9. BioMed Central Full Text
- [10]Basu A, Sivaprasad U: Protein kinase Cε makes the life and death decision. Cell Signal 2007, 19:1633-1642.
- [11]Akita Y: Protein kinase Cepsilon: multiple roles in the function of and signaling mediated by, the cytoskeleton. FEBS J 2008, 275:3995-4004.
- [12]Akita Y: Protein kinase Cε (PKCε): its unique structure and function. J Biochem 2002, 132:847-852.
- [13]Totoń E, Ignatowicz E, Skrzeczkowska K, Rybczyńska M: Protein kinase Cε as a cancer marker and target for anticancer therapy. Pharmacol Rep 2011, 63:19-29.
- [14]Varga A, Czifra G, Tallai B, Németh T, Kovács I, Kovács L, Bíró T: Tumor grade-dependent alterations in the protein kinase C isoform pattern in urinary bladder carcinomas. Eur Urol 2004, 46:462-465.
- [15]Wu D, Foreman TL, Gregory CW, McJilton MA, Wescott GG, Ford OH, Alvey RF, Mohler JL, Terrian DM: Protein kinase cepsilon has the potential to advance the recurrence of human prostate cancer. Cancer Res 2002, 62:2423-2429.
- [16]Pan Q, Bao LW, Kleer CG, Sabel MS, Griffith KA, Teknos TN, Merajver SD: Protein kinase C epsilon is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy. Cancer Res 2005, 65:8366-8371.
- [17]Pan Q, Bao LW, Teknos TN, Merajver SD: Targeted disruption of protein kinase C epsilon reduces cell invasion and motility through inactivation of RhoA and RhoC GTPases in head and neck squamous cell carcinoma. Cancer Res 2006, 66:9379-9384.
- [18]Bae KM, Wang H, Jiang G, Chen MG, Lu L, Xiao L: Protein kinase C epsilon is overexpressed in primary human non-small cell lung cancers and functionally required for proliferation of non-small cell lung cancer cells in a p21/Cip1-dependent manner. Cancer Res 2007, 67:6053-6063.
- [19]Brenner W, Benzing F, Gudejko-Thiel J, Fischer R, Färber G, Hengstler JG, Seliger B, Thüroff JW: Regulation of beta1 integrin expression by PKCepsilon in renal cancer cells. Int J Oncol 2004, 25:1157-1163.
- [20]Engers R, Mrzyk S, Springer E, Fabbro D, Weissgerber G, Gernharz CD, Gabbert HE: Protein kinase C in human renal cell carcinomas: role in invasion and differential isoenzyme expression. Br J Cancer 2000, 82:1063-1069.
- [21]Green FL, Page DL, Fleming ID, et al.: AJCC Cancer Staging Manual. 6th edition. Springer: New York; 2002.
- [22]Fuhrman SA, Lasky LC, Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982, 6:655-663.
- [23]Yamada S, Yanamoto S, Kawasaki G, Rokutanda S, Yonezawa H, Kawakita A, Nemoto TK: Overexpression of CRKII increases migration and invasive potential in oral squamous cell carcinoma. Cancer Letters 2011, 303:84-91.
- [24]Fu L, Qin YR, Xie D, Chow HY, Ngai SM, Kwong DL, Li Y, Guan XY: Identification of alpha-actinin 4 and 67 kDa laminin receptor as stage-specific markers in esophageal cancer via proteomic approaches. Cancer 2007, 110:2672-2681.
- [25]Guo S, Mao X, Chen J, Huang B, Jin C, Xu Z, Qiu S: Overexpression of Pim-1 in bladder cancer. J Exp Clin Cancer Res 2010, 29:161. BioMed Central Full Text
- [26]Pedram A, Razandi M, Wallace DC, Levin ER: Functional estrogen receptors in the mitochondria of breast cancer cells. Mol Biol Cell 2006, 17:2125-37.
- [27]Lu D, Huang J, Basu A: Protein kinase C epsilon activates protein kinase B/Akt via DNA-PK to protect against tumor necrosis factor-alpha-induced cell death. J Biol Chem 2006, 281:22799-22807.
- [28]Hu B, Shen B, Su Y, Geard CR, Balajee AS: Protein kinase C ε is involved in ionizing radiation induced bystander response in human cells. Int J Biochem Cell Biol 2009, 41:2413-2421.
- [29]Wei X, Juan ZX, Min FX, Nan C, Hua ZX, Qing FZ, Zheng L: Recombinant immunotoxin anti-c-Met/PE38KDEL inhibits proliferation and promotes apoptosis of gastric cancer cells. J Exp Clin Cancer Res 2011, 30:67. BioMed Central Full Text
- [30]Zhao CQ, Liu Da, Li Hai, Jiang LS, Dai LY: Interleukin-1b enhances the effect of serum deprivation on rat annular cell apoptosis. Apoptosis 2007, 12:2155-2161.
- [31]Mischak H, Goodnight JA, Kolch W, Martiny-Baron G, Schaechtle C, Kazanietz MG, Blumberg PM, Pierce JH, Mushinski JF: Overexpression of protein kinase C-delta and -epsilon in NIH 3T3 cells induces opposite effects on growth, morphology, anchorage dependence, and tumorigenicity. J Biol Chem 1993, 268:6090-6096.
- [32]Cacace AM, Guadagno SN, Krauss RS, Fabbro D, Weinstein IB: The epsilon isoform of protein kinase C is an oncogene when overexpressed in rat fibroblasts. Oncogene 1993, 8:2095-2104.
- [33]Perletti GP, Folini M, Lin HC, Mischak H, Piccinini F, Tashjian AH Jr: Overexpression of protein kinase C epsilon is oncogenic in rat colonic epithelial cells. Oncogene 1996, 12:847-854.
- [34]Hamilton M, Liao J, Cathcart MK, Wolfman A: Constitutive association of c-N-Ras with c-Raf-1 and protein kinase Cε in latent signaling modules. J Biol Chem 2001, 276:29079-29090.
- [35]Sivaprasad U, Shankar E, Basu A: Protein kinase C-epsilon protects MCF-7 cells from TNF-mediated cell death by inhibiting Bax translocation. Cell Death Differ 2007, 14:851-860.
- [36]McJilton MA, Van Sikes C, Wescott GG: Protein kinase Cepsilon interacts with Bax and promotes survival of human prostate cancer cells. Oncogene 2003, 22:7958-7968.
- [37]Wu D, Thakore CU, Wescott GG, McCubrey JA, Terrian DM: Integrin signaling links protein kinase Cepsilon to the protein kinase B/Akt survival pathway in recurrent prostate cancer cells. Oncogene 2004, 23:8659-8672.
- [38]Hernandez RM, Wescott GG, Mayhew MW, McJilton MA, Terrian DM: Biochemical and morphogenic effects of the interaction between protein kinase C-epsilon and actin in vitro and in cultured NIH3T3 cells. J Cell Biochem 2001, 83:532-546.
- [39]Berrier AL, Mastrangelo AM, Downward J, Ginsberg M, LaFlamme SE: Activated R-ras. Rac1, PI 3-kinase and PKCepsilon can each restore cell spreading inhibited by isolated integrin beta1 cytoplasmic domains. J Cell Biol 2000, 151:1549-1560.
- [40]Hoppe J, Hoppe V, Schafer R: Selective degradation of the PKC-epsilon isoform during cell death in AKR-2B fibroblasts. Exp Cell Res 2001, 266:64-73.
- [41]Mayne GC, Murray AW: Evidence that protein kinase Cepsilon mediates phorbol ester inhibition of calphostin C- and tumor necrosis factor-alpha-induced apoptosis in U937 histiocytic lymphoma cells. J Biol Chem 1998, 273:24115-24121.
- [42]Flescher E, Rotem R: Protein kinase C epsilon mediates the induction of P-glycoprotein in LNCaP prostate carcinoma cells. Cell Signal 2002, 14:37-43.