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TIAM1-RAC1 promote small-cell lung cancer cell survival through antagonizing Nur77-induced BCL2 conformational change

Aishwarya Payapilly1, Ryan Guilbert1, Tine Descamps2

  • 1Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TG, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester, UK.

Cell Reports
|November 10, 2021
PubMed

Insights

TIAM1-RAC1 signaling promotes small-cell lung cancer (SCLC) survival by retaining the Nur77 protein in cell nuclei. Inhibiting this pathway triggers apoptosis, reducing SCLC tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Small-cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with limited treatment options.
  • Acquired resistance to platinum-based chemotherapy is a significant challenge in SCLC management.

Purpose of the Study:

  • To investigate the role of TIAM1 and its downstream effector RAC1 in SCLC cell survival.
  • To elucidate the mechanism by which TIAM1 influences SCLC tumorigenicity and apoptosis.

Main Methods:

  • Analysis of gene expression data from SCLC tumors, patient-derived models, and cell lines.
  • Depletion of TIAM1 and inhibition of RAC1 in SCLC cells.
  • Assessment of cell viability, tumorigenicity, and apoptosis.
  • Investigation of Nur77 protein localization and BCL2 conversion.

Main Results:

  • TIAM1 expression is linked to the neuroendocrine gene program in SCLC.
  • TIAM1 depletion or RAC1 inhibition reduces SCLC cell viability and tumorigenicity.
  • This reduction is mediated by increased apoptosis, involving Nur77 translocation and BCL2 conversion.
  • TIAM1 sequesters Nur77 in the nucleus, and impaired binding abrogates the anti-apoptotic effect.

Conclusions:

  • TIAM1-RAC1 signaling is crucial for SCLC cell survival.
  • Targeting TIAM1-RAC1 may represent a novel therapeutic strategy for SCLC by promoting apoptosis through Nur77 nuclear export.
Keywords:
BCL2Nur77RACSCLCTIAM1apoptosisneuroendocrinesmall cell lung cancer

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