Inhibition of Wnt signaling downregulates Akt activity and induces chemosensitivity in PTEN-mutated prostate cancer cells

T. Ohigashi, Ryuichi Mizuno, J. Nakashima, K. Marumo, M. Murai

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

BACKGROUND. The cross-talk between Wnt signaling and the Akt pathway in prostate cancer (Pca) is still unclear. In the present study, we found that WIF-1 downregulates the Akt pathway and also enhances chemosensitivity in PTEN-null Pca cells. METHODS. Wnt inhibitory factor-1 (WIF-1), an inhibitor of Wnt proteins, was transfected into PC-3 and DU145 Pca cells. RESULTS. Akt was phosphorylated in PTEN-null PC-3 cells but underphosphorylated in PTEN-expressed DU145 cells. The levels of phosphorylated Akt in WIF-1 overexpressing PC-3 cells were lower than those in native or control vector-transfected PC-3 cells. However, WIF-1 showed no additional inhibition of already reduced Akt activity in DU145 cells. Overexpression of WIF-1 resulted in sensitizing PC-3 cells for paclitaxel to induce apoptosis. DU145 cells were more sensitive to paclitaxel but were not affected by WIF-1 transfection. The PI3K inhibitor LY294002 seemed to restore the chemosensitivity of native PC-3 cells like WIF-1 did. CONCLUSIONS. Our results show that Wnt signaling is involved in Akt activation in Pca cells. Our data also indicate the possibility that Wnt and its signaling pathway can be therapeutic targets for PTEN-mutated advanced Pca.

Original languageEnglish
Pages (from-to)61-68
Number of pages8
JournalProstate
Volume62
Issue number1
DOIs
Publication statusPublished - 2005 Jan 1

Fingerprint

Wnt Proteins
Prostatic Neoplasms
Down-Regulation
Wnt Signaling Pathway
Paclitaxel
Wnt1 Protein
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Phosphatidylinositol 3-Kinases
Transfection
Apoptosis

Keywords

  • Akt
  • Paclitaxel
  • Prostate cancer
  • PTEN
  • Wnt signaling

ASJC Scopus subject areas

  • Urology

Cite this

Inhibition of Wnt signaling downregulates Akt activity and induces chemosensitivity in PTEN-mutated prostate cancer cells. / Ohigashi, T.; Mizuno, Ryuichi; Nakashima, J.; Marumo, K.; Murai, M.

In: Prostate, Vol. 62, No. 1, 01.01.2005, p. 61-68.

Research output: Contribution to journalArticle

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AU - Murai, M.

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N2 - BACKGROUND. The cross-talk between Wnt signaling and the Akt pathway in prostate cancer (Pca) is still unclear. In the present study, we found that WIF-1 downregulates the Akt pathway and also enhances chemosensitivity in PTEN-null Pca cells. METHODS. Wnt inhibitory factor-1 (WIF-1), an inhibitor of Wnt proteins, was transfected into PC-3 and DU145 Pca cells. RESULTS. Akt was phosphorylated in PTEN-null PC-3 cells but underphosphorylated in PTEN-expressed DU145 cells. The levels of phosphorylated Akt in WIF-1 overexpressing PC-3 cells were lower than those in native or control vector-transfected PC-3 cells. However, WIF-1 showed no additional inhibition of already reduced Akt activity in DU145 cells. Overexpression of WIF-1 resulted in sensitizing PC-3 cells for paclitaxel to induce apoptosis. DU145 cells were more sensitive to paclitaxel but were not affected by WIF-1 transfection. The PI3K inhibitor LY294002 seemed to restore the chemosensitivity of native PC-3 cells like WIF-1 did. CONCLUSIONS. Our results show that Wnt signaling is involved in Akt activation in Pca cells. Our data also indicate the possibility that Wnt and its signaling pathway can be therapeutic targets for PTEN-mutated advanced Pca.

AB - BACKGROUND. The cross-talk between Wnt signaling and the Akt pathway in prostate cancer (Pca) is still unclear. In the present study, we found that WIF-1 downregulates the Akt pathway and also enhances chemosensitivity in PTEN-null Pca cells. METHODS. Wnt inhibitory factor-1 (WIF-1), an inhibitor of Wnt proteins, was transfected into PC-3 and DU145 Pca cells. RESULTS. Akt was phosphorylated in PTEN-null PC-3 cells but underphosphorylated in PTEN-expressed DU145 cells. The levels of phosphorylated Akt in WIF-1 overexpressing PC-3 cells were lower than those in native or control vector-transfected PC-3 cells. However, WIF-1 showed no additional inhibition of already reduced Akt activity in DU145 cells. Overexpression of WIF-1 resulted in sensitizing PC-3 cells for paclitaxel to induce apoptosis. DU145 cells were more sensitive to paclitaxel but were not affected by WIF-1 transfection. The PI3K inhibitor LY294002 seemed to restore the chemosensitivity of native PC-3 cells like WIF-1 did. CONCLUSIONS. Our results show that Wnt signaling is involved in Akt activation in Pca cells. Our data also indicate the possibility that Wnt and its signaling pathway can be therapeutic targets for PTEN-mutated advanced Pca.

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