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Human lung cancer cell lines exhibit resistance to retinoic acid treatment
J Geradts1, J Y Chen, E K Russell
1National Cancer Institute-Navy Medical Oncology Branch, National Naval Medical Center, Bethesda, Maryland 20889.
Abstract:
Retinoic acid (RA) and nuclear retinoic acid receptors (RARs) have been implicated in a variety of human malignancies including lung cancer, and RA has been proposed as a chemopreventive agent for bronchogenic carcinoma. Normal human tracheobronchial epithelial cells show dramatic induction of RAR-beta mRNA and significant growth inhibition after RA treatment. In contrast, 17 of 22 small cell lung cancer (SCLC) and 9 of 15 non-SCLC lines treated with 1 microM RA showed no significant growth inhibition. Of interest, 5 SCLC lines with high levels of myc gene family expression related to c-, N-, or L-myc gene amplification exhibited growth inhibition (28-87%), whereas 2 non-SCLC lines actually showed growth stimulation after treatment with 1 microM RA. The lines varied greatly in their constitutive expression of RAR-beta mRNA, and 15 of 20 SCLC and 8 of 15 non-SCLC lines failed to show RAR-beta mRNA induction after RA treatment. Six cell lines showed possible alterations in the coding region of RAR-beta by complementary DNA (cDNA)/polymerase chain reaction (PCR) analysis using primers common to the RAR-beta1,2,3 isoforms, since other regions would undergo cDNA/PCR amplification whereas the DNA binding domain would not. Nonetheless, no abnormal band shift patterns in cDNA amplified by PCR were found by single strand conformation polymorphism analysis covering all 1344 base pairs of the RAR-beta open reading frame. Finally, no abnormalities in RAR-alpha gene structure or expression were identified by Southern and Northern blot analysis, including lines with cytogenetic abnormalities of 17q21. We conclude that abnormalities of the RAR-beta system are common in human lung cancer cell lines.
Insights
Retinoic acid (RA) shows potential in preventing lung cancer by inhibiting cell growth. However, many lung cancer cell lines, particularly small cell lung cancer (SCLC), exhibit resistance due to abnormalities in the retinoic acid receptor-beta (RAR-beta) system.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Retinoic acid (RA) and its nuclear receptors (RARs) are involved in human cancers, with RA proposed for lung cancer chemoprevention.
- Normal bronchial cells respond to RA with growth inhibition and RAR-beta mRNA induction.
- Lung cancer cell lines often display resistance to RA's growth-inhibitory effects.
Purpose of the Study:
- To investigate the role and abnormalities of the retinoic acid receptor-beta (RAR-beta) system in human lung cancer cell lines.
- To determine the response of small cell lung cancer (SCLC) and non-SCLC lines to RA treatment.
Main Methods:
- Treatment of lung cancer cell lines (SCLC and non-SCLC) with 1 microM retinoic acid (RA).
- Analysis of cell growth inhibition/stimulation.
- Assessment of RAR-beta mRNA expression and induction using Northern blot.
- Complementary DNA (cDNA)/polymerase chain reaction (PCR) analysis for RAR-beta coding region alterations.
- Single-strand conformation polymorphism (SSCP) analysis of RAR-beta cDNA.
- Southern and Northern blot analysis for RAR-alpha gene structure and expression.
Main Results:
- Most SCLC and non-SCLC lines showed no significant growth inhibition with RA treatment.
- Some SCLC lines with high myc gene expression exhibited growth inhibition, while some non-SCLC lines showed growth stimulation.
- Many SCLC and non-SCLC lines failed to induce RAR-beta mRNA in response to RA.
- No significant abnormalities in RAR-alpha gene structure or expression were detected.
Conclusions:
- Abnormalities in the RAR-beta system are prevalent in human lung cancer cell lines.
- These RAR-beta system abnormalities may contribute to resistance to retinoic acid's therapeutic effects in lung cancer.
- Further research into RAR-beta function and its alterations is crucial for developing effective lung cancer therapies.