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Nodal pathway activation due to Akt1 suppression is a molecular switch for prostate cancer cell

Abdulrahman Alwhaibi1, Arti Verma1, Sandeep Artham1

  • 1Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States.

Biochemical Pharmacology
|June 17, 2019
PubMed

Insights

Akt1 loss in prostate cancer activates the Nodal pathway, promoting metastasis. Inhibiting Nodal may offer a new therapeutic strategy for metastatic prostate cancer (mPCa).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Akt1 plays a negative role in advanced cancers, particularly metastatic prostate cancer (mPCa).
  • Understanding Akt1's role and downstream targets in mPCa is crucial for developing effective treatments.
  • Targeting Akt1 could impact cancer progression and metastasis.

Purpose of the Study:

  • To investigate the consequences of Akt1 deletion in prostate cancer cells.
  • To elucidate the activation of the Nodal pathway by Akt1 loss.
  • To determine the role of the Akt1-FoxO-Nodal axis in prostate cancer epithelial-to-mesenchymal transition (EMT) and metastasis.

Main Methods:

  • Utilized PC3 and DU145 prostate cancer cell lines with Akt1 deletion.
  • Assessed Nodal pathway activation, FoxO1/3a activity, and EMT markers (Snail, N-cadherin, E-cadherin).
  • Employed FoxO inhibitor (AS1842856) and Nodal pathway inhibitor (SB505124).
  • Evaluated cell migration, invasion, and in vivo lung metastasis.
  • Analyzed Nodal mRNA expression and Gleason scores from genomic studies.

Main Results:

  • Akt1 deletion led to increased Nodal expression and FoxO1/3a activation in prostate cancer cells.
  • Akt1 loss promoted EMT, evidenced by increased Snail and N-cadherin and decreased E-cadherin.
  • Inhibition of FoxO abrogated Nodal expression in Akt1-deleted cells.
  • Akt1-deficient cells showed enhanced migration, invasion, and lung metastasis.
  • Nodal pathway inhibition attenuated these metastatic phenotypes.
  • Nodal expression positively correlated with Gleason score in human mPCa.

Conclusions:

  • The Akt1-FoxO3a-Nodal pathway is a significant mediator of prostate cancer metastasis.
  • Nodal pathway activation contributes to prostate cancer EMT and progression.
  • Nodal represents a potential therapeutic target for treating metastatic prostate cancer (mPCa).
Keywords:
Akt1FoxO3aMetastasisNodalProstate cancer

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