Human lung cancer cell lines exhibit resistance to retinoic acid treatment.
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.
Geradts
J
J
National Cancer Institute-Navy Medical Oncology Branch, National Naval Medical Center, Bethesda, Maryland 20889.
Chen
J Y
JY
Russell
E K
EK
Yankaskas
J R
JR
Nieves
L
L
Minna
J D
JD
D001483:Base Sequence; D015139:Blotting, Southern; D002455:Cell Division / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D004351:Drug Resistance; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis*; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D014212:Tretinoin / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014212:Tretinoin