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Calcium signalling links MYC to NUAK1

T Monteverde1, J Tait-Mulder1, A Hedley2

  • 1Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK.

Oncogene
|November 7, 2017
PubMed

Insights

NUAK1 kinase activity is maintained by calcium and PKCα in LKB1-deficient tumor cells, protecting them from MYC-driven death. This reveals a novel role for calcium in tumor cell survival and the NUAK1-MYC synthetic lethal interaction.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Biology

Background:

  • NUAK1 (AMPK-related kinase) regulates cell adhesion, migration, metabolism, and TAU stability.
  • NUAK1 is crucial for tumor cell viability when MYC is overexpressed, despite being activated by tumor suppressor LKB1.
  • The mechanism maintaining NUAK1 activity in LKB1-deficient tumors was previously unknown.

Purpose of the Study:

  • To elucidate the pathway maintaining NUAK1 activity in LKB1-deficient tumor cells.
  • To understand the role of this pathway in tumor cell survival under MYC overexpression.
  • To clarify the synthetic lethal interaction between NUAK1 and MYC.

Main Methods:

  • Investigated NUAK1 activation in LKB1-deficient tumor cells.
  • Utilized biochemical assays to assess kinase activity and signaling pathways.
  • Analyzed the role of calcium, PKCα, and the AMPK-TORC1 pathway.
  • Examined transcriptional regulation by MYC.

Main Results:

  • NUAK1 activity is maintained by calcium-dependent activation of PKCα in LKB1-deficient tumor cells.
  • This calcium/PKCα pathway engages the AMPK-TORC1 metabolic checkpoint, preventing MYC-driven cell death.
  • MYC promotes this survival pathway through transcriptional regulation of PKCα and ITPR.
  • A novel role for calcium in supporting tumor cell viability was identified.

Conclusions:

  • Calcium-dependent activation of NUAK1 via PKCα is a critical survival mechanism in LKB1-deficient, MYC-overexpressing tumors.
  • This pathway represents a potential therapeutic vulnerability in certain cancers.
  • The findings clarify the synthetic lethal interaction between NUAK1 and MYC, highlighting the importance of calcium signaling in cancer metabolism and survival.

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