nach oben

Medical Oncology

Erschienen in:

01.07.2015 | Original Paper

Expression of 3-phosphoinositide-dependent protein kinase 1 in colorectal cancer as a potential therapeutic target

verfasst von: Zhenglei Xu, Bihong Liao, Ru Zhang, Jun Yao, Ruiyue Shi, Lisheng Wang

Erschienen in: Medical Oncology | Ausgabe 7/2015

Einloggen, um Zugang zu erhalten

Abstract

3-Phosphoinositide-dependent protein kinase 1 (PDK1) is centrally involved in cancer progression, including proliferation, apoptosis and invasion. However, its expression pattern and possible cellular functions in human colorectal cancer remain unclear. In the present study, we show that PDK1 expression is up-regulated at both mRNA and protein levels in colorectal cancer clinical specimens and cell lines. Transient knockdown of PDK1 suppresses cellular growth, induces cellular apoptosis and causes abnormal cell cycle distribution. Meanwhile, decreased PDK1 level is closely associated with reduced Akt/cyclin D1 activity. Activating AKT activity and reintroducing cyclin D1 expression significantly compromised the oncogenic activity induced by PDK1. Together, our findings elucidate a key role for PDK1 in colorectal cellular functions trigged by the Akt/cyclin D1 pathway, thus providing a novel insight of PDK1 in colorectal carcinogenesis.

Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29. doi:10.3322/caac.21208.PubMedCrossRef

Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):104–17. doi:10.3322/caac.21220.PubMedCrossRef

Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007;318(5853):1108–13. doi:10.1126/science.1145720.PubMedCrossRef

Mora A, Komander D, van Aalten DM, Alessi DR. PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol. 2004;15(2):161–70.PubMedCrossRef

Biondi RM. Phosphoinositide-dependent protein kinase 1, a sensor of protein conformation. Trends Biochem Sci. 2004;29(3):136–42. doi:10.1016/j.tibs.2004.01.005.PubMedCrossRef

Bayascas JR. Dissecting the role of the 3-phosphoinositide-dependent protein kinase-1 (PDK1) signalling pathways. Cell Cycle. 2008;7(19):2978–82.PubMedCrossRef

Bayascas JR. PDK1: the major transducer of PI 3-kinase actions. Curr Top Microbiol Immunol. 2010;346:9–29. doi:10.1007/82_2010_43.PubMed

Lin HJ, Hsieh FC, Song H, Lin J. Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer. Br J Cancer. 2005;93(12):1372–81. doi:10.1038/sj.bjc.6602862.PubMedCentralPubMedCrossRef

Maurer M, Su T, Saal LH, Koujak S, Hopkins BD, Barkley CR, et al. 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res. 2009;69(15):6299–306. doi:10.1158/0008-5472.CAN-09-0820.PubMedCentralPubMedCrossRef

10.

Zeng X, Xu H, Glazer RI. Transformation of mammary epithelial cells by 3-phosphoinositide-dependent protein kinase-1 (PDK1) is associated with the induction of protein kinase Calpha. Cancer Res. 2002;62(12):3538–43.PubMed

11.

Pearn L, Fisher J, Burnett AK, Darley RL. The role of PKC and PDK1 in monocyte lineage specification by Ras. Blood. 2007;109(10):4461–9. doi:10.1182/blood-2006-09-047217.PubMedCrossRef

12.

Han L, Zhang G, Zhang N, Li H, Liu Y, Fu A, et al. Prognostic potential of microRNA-138 and its target mRNA PDK1 in sera for patients with non-small cell lung cancer. Med Oncol. 2014;31(9):129. doi:10.1007/s12032-014-0129-y.PubMedCrossRef

13.

Ahmed N, Riley C, Quinn MA. An immunohistochemical perspective of PPAR beta and one of its putative targets PDK1 in normal ovaries, benign and malignant ovarian tumours. Br J Cancer. 2008;98(8):1415–24. doi:10.1038/sj.bjc.6604306.PubMedCentralPubMedCrossRef

14.

Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis Int J Program Cell Death. 2004;9(6):667–76. doi:10.1023/B:APPT.0000045801.15585.dd.CrossRef

15.

Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12(1):9–22. doi:10.1016/j.ccr.2007.05.008.PubMedCrossRef

16.

Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261–74. doi:10.1016/j.cell.2007.06.009.PubMedCentralPubMedCrossRef

17.

Nakamura K, Sakaue H, Nishizawa A, Matsuki Y, Gomi H, Watanabe E, et al. PDK1 regulates cell proliferation and cell cycle progression through control of cyclin D1 and p27Kip1 expression. J Biol Chem. 2008;283(25):17702–11. doi:10.1074/jbc.M802589200.PubMedCrossRef

18.

Nawa M, Kanekura K, Hashimoto Y, Aiso S, Matsuoka M. A novel Akt/PKB-interacting protein promotes cell adhesion and inhibits familial amyotrophic lateral sclerosis-linked mutant SOD1-induced neuronal death via inhibition of PP2A-mediated dephosphorylation of Akt/PKB. Cell Signal. 2008;20(3):493–505. doi:10.1016/j.cellsig.2007.11.004.PubMedCrossRef

19.

Sharma RA, Dalgleish AG, Steward WP, O’Byrne KJ. Angiogenesis and the immune response as targets for the prevention and treatment of colorectal cancer (review). Oncol Rep. 2003;10(5):1625–31.PubMed

20.

Russo MW, Wei JT, Thiny MT, Gangarosa LM, Brown A, Ringel Y, et al. Digestive and liver diseases statistics, 2004. Gastroenterology. 2004;126(5):1448–53.PubMedCrossRef

21.

Littlejohns P, Tamber S, Ranson P, Campbell B. Treatment for liver metastases from colorectal cancer. Lancet Oncol. 2005;6(2):73.PubMedCrossRef

22.

Weitz J, Koch M, Debus J, Hohler T, Galle PR, Buchler MW. Colorectal Cancer. Lancet. 2005;365(9454):153–65. doi:10.1016/S0140-6736(05)17706-X.PubMedCrossRef

23.

Pearce LR, Komander D, Alessi DR. The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol. 2010;11(1):9–22. doi:10.1038/nrm2822.PubMedCrossRef

24.

Wick MJ, Ramos FJ, Chen H, Quon MJ, Dong LQ, Liu F. Mouse 3-phosphoinositide-dependent protein kinase-1 undergoes dimerization and trans-phosphorylation in the activation loop. J Biol Chem. 2003;278(44):42913–9. doi:10.1074/jbc.M304172200.PubMedCrossRef

25.

Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Current Biol. 1997;7(4):261–9.CrossRef

26.

Leslie NR, Yang X, Downes CP, Weijer CJ. The regulation of cell migration by PTEN. Biochem Soc Trans. 2005;33(Pt 6):1507–8. doi:10.1042/BST20051507.PubMed

27.

Lim MA, Yang L, Zheng Y, Wu H, Dong LQ, Liu F. Roles of PDK-1 and PKN in regulating cell migration and cortical actin formation of PTEN-knockout cells. Oncogene. 2004;23(58):9348–58. doi:10.1038/sj.onc.1208147.PubMedCrossRef

28.

Rodriguez OC, Lai EW, Vissapragada S, Cromelin C, Avetian M, Salinas P, et al. A reduction in Pten tumor suppressor activity promotes ErbB-2-induced mouse prostate adenocarcinoma formation through the activation of signaling cascades downstream of PDK1. Am J Pathol. 2009;174(6):2051–60. doi:10.2353/ajpath.2009.080859.PubMedCentralPubMedCrossRef

29.

Nagashima K, Shumway SD, Sathyanarayanan S, Chen AH, Dolinski B, Xu Y, et al. Genetic and pharmacological inhibition of PDK1 in cancer cells: characterization of a selective allosteric kinase inhibitor. J Biol Chem. 2011;286(8):6433–48. doi:10.1074/jbc.M110.156463.PubMedCentralPubMedCrossRef

30.

Liu Y, Wang J, Wu M, Wan W, Sun R, Yang D, et al. Down-regulation of 3-phosphoinositide-dependent protein kinase-1 levels inhibits migration and experimental metastasis of human breast cancer cells. Mol Cancer Res. 2009;7(6):944–54. doi:10.1158/1541-7786.MCR-08-0368.PubMedCrossRef

31.

Finlay DK, Sinclair LV, Feijoo C, Waugh CM, Hagenbeek TJ, Spits H, et al. Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes. J Exp Med. 2009;206(11):2441–54. doi:10.1084/jem.20090219.PubMedCentralPubMedCrossRef

32.

Pinner S, Sahai E. PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE. Nat Cell Biol. 2008;10(2):127–37. doi:10.1038/ncb1675.PubMedCrossRef

33.

Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, et al. Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. Biochem J. 1999;337(Pt 3):575–83.PubMedCentralPubMedCrossRef

34.

Milburn CC, Deak M, Kelly SM, Price NC, Alessi DR, Van Aalten DM. Binding of phosphatidylinositol 3,4,5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change. Biochem J. 2003;375(Pt 3):531–8. doi:10.1042/BJ20031229.PubMedCentralPubMedCrossRef

35.

Calleja V, Ameer-Beg SM, Vojnovic B, Woscholski R, Downward J, Larijani B. Monitoring conformational changes of proteins in cells by fluorescence lifetime imaging microscopy. Biochem J. 2003;372(Pt 1):33–40. doi:10.1042/BJ20030358.PubMedCentralPubMedCrossRef

36.

Stacey DW. Cyclin D1 serves as a cell cycle regulatory switch in actively proliferating cells. Curr Opin Cell Biol. 2003;15(2):158–63.PubMedCrossRef

Titel: Expression of 3-phosphoinositide-dependent protein kinase 1 in colorectal cancer as a potential therapeutic target
verfasst von: Zhenglei Xu
Bihong Liao
Ru Zhang
Jun Yao
Ruiyue Shi
Lisheng Wang
Publikationsdatum: 01.07.2015
Verlag: Springer US
Erschienen in: Medical Oncology / Ausgabe 7/2015
Print ISSN: 1357-0560
Elektronische ISSN: 1559-131X
DOI: https://doi.org/10.1007/s12032-015-0645-4

Neu im Fachgebiet Onkologie

23.04.2024 | Medikamente in Schwangerschaft und Stillzeit | Nachrichten

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Expression of 3-phosphoinositide-dependent protein kinase 1 in colorectal cancer as a potential therapeutic target

Abstract

Neu im Fachgebiet Onkologie

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Stufenschema weist Prostatakarzinom zuverlässig nach

Update Onkologie

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 7/2015

The c-Myc–LDHA axis positively regulates aerobic glycolysis and promotes tumor progression in pancreatic cancer

Influence of an elevated nutrition risk score (NRS) on survival in patients following gastrectomy for gastric cancer

Human telomerase reverse transcriptase regulates vascular endothelial growth factor expression via human papillomavirus oncogene E7 in HPV-18-positive cervical cancer cells

Erratum to: Effect of circulating tumor cells combined with negative enrichment and CD45-FISH identification in diagnosis, therapy monitoring and prognosis of primary lung cancer

Dysregulated expression of Dicer in invasive ductal breast carcinoma

Peptide GE11–Polyethylene Glycol–Polyethylenimine for targeted gene delivery in laryngeal cancer

Neu im Fachgebiet Onkologie

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Stufenschema weist Prostatakarzinom zuverlässig nach

Update Onkologie