Enhancement of Calu-1 human lung carcinoma cell growth in serum-free medium by retinoids: dependence on AP-1 activation, but not on retinoid response element activation

Oncogene. 1997 Oct 23;15(17):2109-18. doi: 10.1038/sj.onc.1201381.


Many lung cancer cell lines are resistant to the growth inhibitory effects of retinoids. However, some small-cell lung cancer cell lines were inhibited by all trans-retinoic acid (ATRA) in serum-free medium. We compared the responses of seven non-small cell lung cancer (NSCLC) cell lines to ATRA in serum-free medium and in medium supplemented with delipidized serum. Whereas the growth of four cell lines was inhibited more in serum-free medium, the growth of the Calu-1 cell line was stimulated by ATRA in a dose-dependent fashion with a maximum at 10(-8) M. Delipidized serum (>2.5%) but not bovine serum albumin (0.15%) suppressed growth stimulation by ATRA. Transcripts of RA receptors RARalpha and RARgamma but not of RARbeta were detected in Calu-1 cells. Receptor expression, the formation of a complex among receptors and a RA-responsive element (RARE), and the transcriptional activation RARE were not suppressed by serum. Natural retinoids and synthetic receptor class- or subtype-selective retinoid agonists, which activated RARs and RXRs for gene transcription from a RARE, and a RAR antagonist (CD2366), which was unable to do so, stimulated the growth of Calu-1 cells in serum-free medium but not in serum-containing medium. Both ATRA and CD2366 enhanced the transcriptional activation of an Activator Protein-1 (AP-1)-luciferase reporter construct in serum-free medium but not in delipidized serum. Transcriptional activation of the RARE by ATRA occurred both in the presence or absence of delipidized serum. These results demonstrate that retinoid-induced growth stimulation of Calu-1 cells is associated with enhanced AP-1 transactivation but not with RARE transactivation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Benzoates* / pharmacology
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Division / drug effects
  • Cell Nucleus / metabolism
  • Culture Media / chemistry
  • Culture Media, Serum-Free
  • Drug Resistance, Neoplasm
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Neoplasm Proteins / metabolism*
  • Receptors, Retinoic Acid / antagonists & inhibitors
  • Receptors, Retinoic Acid / drug effects*
  • Receptors, Retinoic Acid / metabolism
  • Retinoids / pharmacology
  • Tetrahydronaphthalenes / pharmacology
  • Transcription Factor AP-1 / metabolism*
  • Transcriptional Activation / drug effects
  • Tretinoin / metabolism
  • Tretinoin / pharmacology*
  • Tumor Cells, Cultured / drug effects


  • Antineoplastic Agents
  • Benzoates
  • Culture Media
  • Culture Media, Serum-Free
  • Neoplasm Proteins
  • Receptors, Retinoic Acid
  • Retinoids
  • Tetrahydronaphthalenes
  • Transcription Factor AP-1
  • SR 11217
  • SR 11234
  • Tretinoin