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Inactivation of PI3K-C2α deregulates cell death pathways and sensitizes to endotoxic shock

York Posor1,2, Sarah E Conduit1, Wayne Pearce1

  • 1Department of Oncology, University College London (UCL) Cancer Institute, University College London, London WC1E 6DD, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|July 17, 2025
PubMed

Insights

Systemic inactivation of PI3K-C2α is well tolerated in mice but unexpectedly sensitizes them to bacterial lipopolysaccharide (LPS) challenge, revealing a novel role in regulating cell death pathways.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Immunology

Background:

  • The roles of class II phosphoinositide 3-kinase (PI3K) isoform PI3K-C2α are not fully understood.
  • PI3K-C2α has been implicated in arterial thrombosis and breast cancer metastasis, making it a potential drug target.
  • The effects of systemic PI3K-C2α inactivation in healthy adult states are largely unknown.

Purpose of the Study:

  • To investigate the physiological consequences of systemic PI3K-C2α inactivation in adult mice.
  • To explore the role of PI3K-C2α in response to bacterial lipopolysaccharide (LPS) challenge.
  • To elucidate the mechanisms underlying PI3K-C2α's function in cell death regulation.

Main Methods:

  • Genetic inactivation of PI3K-C2α in adult mice.
  • Administration of bacterial lipopolysaccharide (LPS) to induce endotoxic shock.
  • Vascular endothelial-specific deletion of PI3K-C2α.
  • Genetic manipulation to disable extrinsic cell death pathways (caspase-8 and RIPK3 deficiency).

Main Results:

  • Systemic PI3K-C2α inactivation was well tolerated in adult mice without apparent physiological impairment.
  • Mice lacking PI3K-C2α exhibited heightened sensitivity to LPS-induced endotoxic shock.
  • This LPS sensitization was also observed in mice with vascular endothelial-specific PI3K-C2α deletion.
  • Sensitization to LPS was fully reversed by concurrently disabling extrinsic cell death pathways.

Conclusions:

  • Systemic PI3K-C2α inhibition is a potentially viable therapeutic strategy.
  • PI3K-C2α plays a critical, previously unrecognized role in regulating extrinsic cell death pathways.
  • Targeting PI3K-C2α may offer new avenues for managing conditions involving endotoxic shock and dysregulated cell death.
Keywords:
PI3Kendotoxic shockphosphoinositideregulated cell deathvascular endothelia

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