PP2A regulates metastasis and vasculogenic mimicry formation via PI3K/AKT/ZEB1 axis in non-small cell lung cancers

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Tyrosine kinase inhibitor resistance in non-small cell lung cancer (NSCLC) is a significant clinical challenge.
• Vasculogenic mimicry (VM) promotes tumor progression and drug resistance in NSCLC.
• The role of protein phosphatase 2A (PP2A), a tumor suppressor, in NSCLC VM and invasion is not well understood.

Purpose of the Study:

• To investigate the role of PP2A in regulating VM formation and invasion in NSCLC.
• To elucidate the underlying molecular mechanisms by which PP2A affects VM.

Main Methods:

• In vitro and in vivo experiments using NSCLC cell lines and xenograft models.
• Activation or inhibition of PP2A using specific agents (FTY720, Ad-PP2A, okadaic acid, Ad-dn-PP2A).
• Analysis of signaling pathways including PI3K/AKT/ZEB1 and expression of key proteins (p-AKT, ZEB1, MMP-2, VE-cadherin, VEGFR-2).
• Combination therapy with a PI3K inhibitor (BENC-511).

Main Results:

• PP2A activation significantly inhibited VM formation, invasion, and migration in NSCLC.
• PP2A reduced phosphorylated AKT and ZEB1 transcription, leading to decreased expression of MMP-2, VE-cadherin, and VEGFR-2.
• PP2A inhibition produced opposite effects, promoting VM and invasion.
• PP2A reactivation suppressed tumor growth and VM in a xenograft model.
• Combination with a PI3K inhibitor potentiated PP2A activation, further inhibiting p-AKT/ZEB1 and VM.

Conclusions:

• PP2A regulates VM formation in NSCLC via the PI3K/AKT/ZEB1 signaling axis.
• Reactivation of PP2A or its combination with PI3K inhibitors represents a potential therapeutic strategy for advanced NSCLC by targeting VM.