Apoptosis

, Volume 19, Issue 1, pp 179–190 | Cite as

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

  • Kyoung-Jae Won
  • Bo Kyung Kim
  • Gyoonhee Han
  • Kyeong Lee
  • Young-Jin Jung
  • Hwan-Mook Kim
  • Kyung Bin Song
  • Kyung-Sook Chung
  • Misun Won
Original Paper

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.

Keywords

Apoptosis Akt FoxO3a RhoB NSC126188 

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

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Kyoung-Jae Won
    • 1
    • 2
  • Bo Kyung Kim
    • 1
  • Gyoonhee Han
    • 3
  • Kyeong Lee
    • 4
  • Young-Jin Jung
    • 1
    • 2
  • Hwan-Mook Kim
    • 5
  • Kyung Bin Song
    • 6
  • Kyung-Sook Chung
    • 1
  • Misun Won
    • 1
    • 2
  1. 1.Medical Genome Research CenterKRIBBTaejonKorea
  2. 2.Department of Functional GenomicsUniversity of Science and TechnologyTaejonKorea
  3. 3.Department of BiotechnologyYeonsei UniversitySeoulKorea
  4. 4.Dongguk University-SeoulSeoulKorea
  5. 5.College of PharmacyGachon UniversityIncheonKorea
  6. 6.Department of Food Science and TechnologyChungnam National UniversityTaejonKorea

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