Temporal Phosphoproteome Dynamics Induced by an ATP Synthase Inhibitor Citreoviridin

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Citreoviridin is a mycotoxin that inhibits lung cancer cell growth by targeting ATP synthase.
• The precise molecular mechanisms by which citreoviridin induces cellular responses in cancer cells are not fully understood.

Purpose of the Study:

• To elucidate the dynamic molecular responses triggered by citreoviridin in cancer cells using temporal phosphoproteomics.
• To identify key signaling pathways and protein modifications involved in citreoviridin's anti-cancer effects.

Main Methods:

• Temporal phosphoproteomics was employed to analyze dynamic changes in protein phosphorylation after citreoviridin treatment in vitro and in a xenograft model.
• Mathematical modeling was used to construct a response network and identify relationships between key signaling molecules.

Main Results:

• A total of 829 phosphoproteins were identified, indicating citreoviridin affects protein folding, cell cycle, and cytoskeleton functions.
• A response network revealed a link between phosphorylated heat shock protein 90 beta (HSP90AB1) and the mitogen-activated protein kinase (MAPK) signaling pathway.
• Citreoviridin was shown to suppress cancer cell growth and MAPK/extracellular signal-regulated kinase (ERK) signaling via site-specific dephosphorylation of HSP90AB1 at Serine 255.

Conclusions:

• Citreoviridin suppresses lung cancer cell proliferation and MAPK/ERK signaling through the dephosphorylation of HSP90AB1.
• This study provides novel insights into the molecular mechanisms of citreoviridin and suggests its potential as a cancer therapeutic strategy.