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Guanosine triphosphate links MYC-dependent metabolic and ribosome programs in small-cell lung cancer

Fang Huang1,2, Kenneth E Huffman3, Zixi Wang2

  • 1Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The Journal of Clinical Investigation
|October 20, 2020
PubMed

Insights

MYC drives cancer growth by linking metabolism and protein synthesis via guanosine triphosphate (GTP). This creates a vulnerability in chemoresistant small-cell lung cancer (SCLC) cells, targeting inosine monophosphate dehydrogenase (IMPDH).

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Regulation

Background:

  • The MYC oncogene stimulates cellular metabolism and protein synthesis, but the coordination mechanism remains unclear.
  • Previous studies linked MYC to guanosine triphosphate (GTP) synthesis and sensitivity to inosine monophosphate dehydrogenase (IMPDH) inhibitors in some small-cell lung cancer (SCLC) cell lines.

Purpose of the Study:

  • To investigate how MYC coordinates metabolic and protein synthesis programs.
  • To explore the role of GTP and IMPDH in MYC-driven SCLC, particularly in chemoresistant cases.

Main Methods:

  • Analysis of guanosine nucleotide levels in primary MYC-high (MYChi) human SCLC tumors.
  • Investigating the functional link between IMPDH, GTP, and ribosome biogenesis.
  • Examining the role of GTPases GPN1 and GPN3 in regulating RNA polymerase I (Pol I) localization.

Main Results:

  • Primary MYChi SCLC tumors exhibit abundant guanosine nucleotides.
  • Acquired chemoresistance in SCLC elevates MYC, inducing dependence on IMPDH.
  • IMPDH acts as a crucial link between MYC's metabolic and protein synthesis outputs, regulating Pol I localization via GTP and GPN1/3.

Conclusions:

  • GTP acts as a metabolic gatekeeper, coupling MYC-driven ribosome biogenesis to nucleotide availability through GPN1 and GPN3.
  • IMPDH dependence represents a targetable vulnerability in chemoresistant MYChi SCLC.
Keywords:
Intermediary metabolismLung cancerMetabolismOncogenesOncology

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