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Mechanistic insights into cancer drug resistance through optogenetic PI3K signaling hyperactivation

Yoshibumi Ueda1, Yuri Miura2, Nario Tomishige3

  • 1Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan.

Cell Chemical Biology
|October 26, 2022
PubMed

Insights

Cancer cells resist drugs by activating phosphatidylinositol 3-kinase (PI3K) signaling, leading to increased tumor necrosis factor alpha-induced protein 8 (TNFAIP8) expression. This occurs via protein translation from existing mRNA, enabling survival despite DNA damage.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Hyperactivation of phosphatidylinositol 3-kinase (PI3K) signaling is common in cancer.
  • The mechanisms driving cancer's malignant behaviors under PI3K hyperactivation are not fully understood.

Purpose of the Study:

  • To elucidate the mechanism of cancer drug resistance downstream of PI3K signaling.
  • To investigate the role of protein synthesis in mediating resistance.

Main Methods:

  • Development of an optogenetic tool (PPAP2) to control PI3K signaling.
  • Utilizing melanoma cells (A375-PPAP2) engineered to express PPAP2.
  • Performing proteome analyses to identify upregulated proteins.

Main Results:

  • A375-PPAP2 cells exhibited resistance to a cancer drug when PI3K signaling was hyperactivated.
  • Proteome analysis revealed upregulation of the antiapoptotic factor tumor necrosis factor alpha-induced protein 8 (TNFAIP8).
  • TNFAIP8 upregulation was confirmed to be mediated by translation from preexisting mRNA.

Conclusions:

  • Cancer cells can evade drug-induced death by upregulating TNFAIP8 expression from existing mRNA.
  • This mechanism provides a survival advantage even when DNA is damaged by alkylating agents.
  • Protein synthesis pathways play a critical role in cancer drug resistance downstream of PI3K signaling.
Keywords:
PI3K signalingPIP3TNFAIP8cancer drug resistanceoptogeneticsphosphatidylinositol 3,4,5-trisphosphate

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