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Growth suppression of lung cancer cells by targeting cyclic AMP response element-binding protein

Sita Aggarwal1, Seung-Wook Kim, Seung-Hee Ryu

  • 1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Cancer Research
|February 19, 2008
PubMed

Insights

Cyclic AMP-response element-binding protein (CREB) is highly active in non-small cell lung cancer (NSCLC) and drives tumor growth. Inhibiting CREB signaling effectively suppressed NSCLC cell proliferation and induced apoptosis, suggesting CREB as a therapeutic target.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • Cyclic AMP-response element-binding protein (CREB) regulates genes involved in apoptosis suppression, cell proliferation, inflammation, and tumor metastasis.
  • The specific role of CREB in lung carcinogenesis remains unclear.
  • Non-small cell lung cancer (NSCLC) cell lines show elevated activity of CREB and its upstream kinases, as well as CREB-regulated survival proteins like Bcl-2 and Bcl-xL.

Purpose of the Study:

  • To investigate the role of constitutively active CREB in NSCLC cell growth and survival.
  • To evaluate CREB as a potential therapeutic target for NSCLC.

Main Methods:

  • Assessed CREB activity and expression of related proteins in NSCLC cell lines.
  • Utilized dominant repressor CREB and small interfering RNA (siRNA) against CREB to inhibit cell growth and survival.
  • Administered Ro-31-8220, a CREB signaling pathway inhibitor, to NSCLC cells to assess its effects on cell cycle, apoptosis, and protein expression.
  • Compared the cytotoxic effects of Ro-31-8220 on NSCLC cells versus normal bronchial epithelial cells.

Main Results:

  • NSCLC cell lines exhibited elevated constitutive activity of CREB, ribosomal s6 kinase, extracellular signal kinase, Bcl-2, and Bcl-xL.
  • Inhibition of CREB activity via dominant repressor or siRNA suppressed NSCLC cell growth and survival, inducing apoptosis.
  • Ro-31-8220 treatment inhibited CREB activation, arrested the cell cycle at G(2)-M phase, induced apoptosis, and suppressed Bcl-2/Bcl-xL expression.
  • Ro-31-8220 effectively suppressed both anchorage-dependent and independent NSCLC cell growth with less toxicity to normal bronchial epithelial cells.

Conclusions:

  • Active CREB plays a critical role in the growth and survival of NSCLC cells.
  • Inhibitors of CREB activation represent a promising therapeutic strategy for NSCLC treatment.

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