Skip to main content
SpringerLink
Log in

NSC126188 induces apoptosis of prostate cancer PC-3 cells through inhibition of Akt membrane translocation, FoxO3a activation, and RhoB transcription

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

We previously reported that NSC126188 caused apoptosis of cancer cells by inducing expression of RhoB. We here present that NSC126188 induces apoptosis of prostate cancer PC-3 cells by inhibiting Akt/FoxO3 signaling, which mediates RhoB upregulation. The apoptosis and Akt dephosphorylation caused by NSC126188 was not substantially relieved by overexpressing wild-type Akt but was relieved by overexpressing constitutively active Akt (CA-Akt) or myristoylated Akt (myr-Akt). Furthermore, overexpression of CA-Akt or myr-Akt downregulated RhoB expression, indicating that RhoB expression is regulated by Akt signaling. Interestingly, membrane translocation of GFP-Akt by insulin exposure was abolished in the cells pretreated with NSC126188 suggesting that NSC126188 directly interfered with translocation of Akt to the plasma membrane. In addition, NSC126188 activated FoxO3a by dephosphorylating S253 via Akt inhibition. Activated FoxO3a translocated to the nucleus and increased transcription of RhoB and other target genes. PC-3 cells transiently overexpressing FoxO3a exhibited increased RhoB expression and apoptosis in response to NSC126188. Conversely, FoxO3a knockdown reduced NSC126188-induced RhoB expression and cell death. These results suggest that RhoB may be a target gene of FoxO3a and is regulated by Akt signaling. Taken together, NSC126188 induces apoptosis of PC-3 cells by interfering with membrane recruitment of Akt, resulting in Akt dephosphorylation and FoxO3a activation, which leads to transcription of RhoB.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

CA-Akt:

Constitutively active Akt

myr-Akt:

Myristrated Akt

PI3K:

Phosphoinositide 3-kinase

SAPK/JNK:

Stress-activated protein kinase/c-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

PH domain:

Pleckstrin homology domain

PDK1:

Phosphoinositide-dependent protein kinase 1

mTORC2:

Mammalian target of rapamycin complex 2

PTEN:

Phosphatase and tensin homolog

HDAC:

Histone deacetylase

PIP3 :

Phosphatidylinositol 3,4,5-trisphosphate

PIP2 :

Phosphatidylinositol (3,4)-bisphosphate

FoxO:

Forkhead box O

HAT:

Histone acetylase

HDAC1:

Histone deacetylase 1

References

  1. Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7):1261–1274

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100(4):387–390

    Article  PubMed  Google Scholar 

  3. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7(4):261–269

    Article  CAS  PubMed  Google Scholar 

  4. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101

    Article  CAS  PubMed  Google Scholar 

  5. Kohn AD, Takeuchi F, Roth RA (1996) Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem 271(36):21920–21926

    Article  CAS  PubMed  Google Scholar 

  6. Bellacosa A, Chan TO, Ahmed NN, Datta K, Malstrom S, Stokoe D, McCormick F, Feng J, Tsichlis P (1998) Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 17(3):313–325

    Article  CAS  PubMed  Google Scholar 

  7. Huang H, Tindall DJ (2007) Dynamic FoxO transcription factors. J Cell Sci 120(Pt 15):2479–2487

    Article  CAS  PubMed  Google Scholar 

  8. Sundaresan NR, Pillai VB, Wolfgeher D, Samant S, Vasudevan P, Parekh V, Raghuraman H, Cunningham JM, Gupta M, Gupta MP (2011) The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci Signal 4(182):46

    Article  Google Scholar 

  9. Kondapaka SB, Singh SS, Dasmahapatra GP, Sausville EA, Roy KK (2003) Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2(11):1093–1103

    CAS  PubMed  Google Scholar 

  10. Meuillet EJ, Zuohe S, Lemos R, Ihle N, Kingston J, Watkins R, Moses SA, Zhang S, Du-Cuny L, Herbst R et al (2010) Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor. Mol Cancer Ther 9(3):706–717

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Prendergast GC (2001) Actin’ up: RhoB in cancer and apoptosis. Nat Rev 1(2):162–168

    Article  CAS  Google Scholar 

  12. Huang M, Prendergast GC (2006) RhoB in cancer suppression. Histol Histopathol 21(2):213–218

    CAS  PubMed  Google Scholar 

  13. Jiang K, Sun J, Cheng J, Djeu JY, Wei S, Sebti S (2004) Akt mediates Ras downregulation of RhoB, a suppressor of transformation, invasion, and metastasis. Mol Cell Biol 24(12):5565–5576

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Kim BK, Kim HM, Chung KS, Kim DM, Park SK, Song A, Won KJ, Lee K, Oh YK, Lee K et al (2011) Upregulation of RhoB via c-Jun N-terminal kinase signaling induces apoptosis of the human gastric carcinoma NUGC-3 cells treated with NSC12618. Carcinogenesis 32(3):254–261

    Article  PubMed  Google Scholar 

  15. Kim BK, Kim DM, Chung KS, Park SK, Choi SJ, Song A, Lee K, Lee CW, Song KB, Han G et al (2011) NSC126188, a piperazine alkyl derivative, induces apoptosis via upregulation of RhoB in HeLa cells. Invest New Drugs 29(5):853–860

    Article  CAS  PubMed  Google Scholar 

  16. Won MS, Im N, Park S, Boovanahalli SK, Jin Y, Jin X, Chung KS, Kang M, Lee K, Park SK et al (2009) A novel benzimidazole analogue inhibits the hypoxia-inducible factor (HIF)-1 pathway. Biochem Biophys Res Commun 385(1):16–21

    Article  CAS  PubMed  Google Scholar 

  17. Kim DM, Koo SY, Jeon K, Kim MH, Lee J, Hong CY, Jeong S (2003) Rapid induction of apoptosis by combination of flavopiridol and tumor necrosis factor (TNF)-alpha or TNF-related apoptosis-inducing ligand in human cancer cell lines. Cancer Res 63(3):621–626

    CAS  PubMed  Google Scholar 

  18. Chung KS, Jang YJ, Kim NS, Park SY, Choi SJ, Kim JY, Ahn JH, Lee HJ, Lim JH, Song JH et al (2007) Rapid screen of human genes for relevance to cancer using fission yeast. J Biomol Screen 12(4):568–577

    Article  CAS  PubMed  Google Scholar 

  19. Liu QY, Rubin MA, Omene C, Lederman S, Stein CA (1998) Fas ligand is constitutively secreted by prostate cancer cells in vitro. Clin Cancer Res 4(7):1803–1811

    CAS  PubMed  Google Scholar 

  20. Chung KS, Yim NH, Lee SH, Choi SJ, Hur KS, Hoe KL, Kim DU, Goehle S, Kim HB, Song KB et al (2008) Identification of small molecules inducing apoptosis by cell-based assay using fission yeast deletion mutants. Invest New Drugs 26(4):299–307

    Article  CAS  PubMed  Google Scholar 

  21. Kim DM, Chung KS, Choi SJ, Jung YJ, Park SK, Han GH, Ha JS, Song KB, Choi NS, Kim HM et al (2009) RhoB induces apoptosis via direct interaction with TNFAIP1 in HeLa cells. Int J Cancer 125(11):2520–2527

    Article  CAS  PubMed  Google Scholar 

  22. Dignam JD, Lebovitz RM, Roeder RG (1983) Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11(5):1475–1489

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C et al (2010) Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One 5(3):e9646

    Article  PubMed Central  PubMed  Google Scholar 

  24. Hu L, Zaloudek C, Mills GB, Gray J, Jaffe RB (2000) In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Clin Cancer Res 6(3):880–886

    CAS  PubMed  Google Scholar 

  25. Wang S, Yan-Neale Y, Fischer D, Zeremski M, Cai R, Zhu J, Asselbergs F, Hampton G, Cohen D (2003) Histone deacetylase 1 represses the small GTPase RhoB expression in human nonsmall lung carcinoma cell line. Oncogene 22(40):6204–6213

    Article  CAS  PubMed  Google Scholar 

  26. Mazieres J, Antonia T, Daste G, Muro-Cacho C, Berchery D, Tillement V, Pradines A, Sebti S, Favre G (2004) Loss of RhoB expression in human lung cancer progression. Clin Cancer Res 10(8):2742–2750

    Article  CAS  PubMed  Google Scholar 

  27. Marlow LA, Reynolds LA, Cleland AS, Cooper SJ, Gumz ML, Kurakata S, Fujiwara K, Zhang Y, Sebo T, Grant C et al (2009) Reactivation of suppressed RhoB is a critical step for the inhibition of anaplastic thyroid cancer growth. Cancer Res 69(4):1536–1544

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Couderc B, Pradines A, Rafii A, Golzio M, Deviers A, Allal C, Berg D, Penary M, Teissie J, Favre G (2008) In vivo restoration of RhoB expression leads to ovarian tumor regression. Cancer Gene Ther 15(7):456–464

    Article  CAS  PubMed  Google Scholar 

  29. Pinton G, Manente AG, Angeli G, Mutti L, Moro L (2012) Perifosine as a potential novel anti-cancer agent inhibits EGFR/MET-AKT axis in malignant pleural mesothelioma. PLoS One 7(5):e36856

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Hennessy BT, Lu Y, Poradosu E, Yu Q, Yu S, Hall H, Carey MS, Ravoori M, Gonzalez-Angulo AM, Birch R et al (2007) Pharmacodynamic markers of perifosine efficacy. Clin Cancer Res 13(24):7421–7431

    Article  CAS  PubMed  Google Scholar 

  31. Gills JJ, Dennis PA (2009) Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep 11(2):102–110

    Article  CAS  PubMed  Google Scholar 

  32. Liu P, Cheng H, Roberts TM, Zhao JJ (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8(8):627–644

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Gills JJ, Holbeck S, Hollingshead M, Hewitt SM, Kozikowski AP, Dennis PA (2006) Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt. Mol Cancer Ther 5(3):713–722

    Article  CAS  PubMed  Google Scholar 

  34. Zhang X, Tang N, Hadden TJ, Rishi AK (2011) Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 11:1978–1986

    Article  Google Scholar 

  35. Yang JY, Hung MC (2009) A new fork for clinical application: targeting forkhead transcription factors in cancer. Clin Cancer Res 15(3):752–757

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Kamasani U, Duhadaway JB, Alberts AS, Prendergast GC (2007) mDia function is critical for the cell suicide program triggered by farnesyl transferase inhibition. Cancer Biol Ther 6(9):1422–1427

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work is supported by Ministry of Education, Science and Technology (NRF-2010-0025517; NRF-2012-0007275), the 21st Century Frontier for Functional Analysis of the Human Genome (FG09-31-02), and KRIBB Initiative of the Korea Research Council of Fundamental Science and Technology.

Disclosure

The authors declare that they do not have any disclosures.

Author information

Authors and Affiliations

  1. Medical Genome Research Center, KRIBB, Taejon, 305-806, Korea

    Kyoung-Jae Won, Bo Kyung Kim, Young-Jin Jung, Kyung-Sook Chung & Misun Won

  2. Department of Functional Genomics, University of Science and Technology, Taejon, 305-350, Korea

    Kyoung-Jae Won, Young-Jin Jung & Misun Won

  3. Department of Biotechnology, Yeonsei University, Seoul, 129-749, Korea

    Gyoonhee Han

  4. Dongguk University-Seoul, Seoul, 100-715, Korea

    Kyeong Lee

  5. College of Pharmacy, Gachon University, Incheon, 406-840, Korea

    Hwan-Mook Kim

  6. Department of Food Science and Technology, Chungnam National University, Taejon, 305-764, Korea

    Kyung Bin Song

Authors
  1. Kyoung-Jae Won
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bo Kyung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gyoonhee Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyeong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Young-Jin Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hwan-Mook Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kyung Bin Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kyung-Sook Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Misun Won
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kyung-Sook Chung or Misun Won.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Won, KJ., Kim, B.K., Han, G. et al. NSC126188 induces apoptosis of prostate cancer PC-3 cells through inhibition of Akt membrane translocation, FoxO3a activation, and RhoB transcription. Apoptosis 19, 179–190 (2014). https://doi.org/10.1007/s10495-013-0905-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-013-0905-8

Keywords

Search

Navigation