Glucocorticoid receptor over-expression promotes human small cell lung cancer apoptosis in vivo and thereby slows tumor growth.
Small cell lung cancer (SCLC) is an aggressive tumor, associated with ectopic ACTH syndrome. We have shown that SCLC cells are glucocorticoid receptor (GR) deficient, and that restoration of GR expression confers glucocorticoid sensitivity and induces apoptosis in vitro. To determine the effects of GR expression in vivo, we characterized a mouse SCLC xenograft model that secretes ACTH precursor peptides, and so drives high circulating corticosterone concentrations (analogous to the ectopic ACTH syndrome). Infection of SCLC xenografts with GR-expressing adenovirus significantly slowed tumor growth compared with control virus infection. Time to fourfold initial tumor volume increased from a median of 9 days to 16 days (P=0.05; n=7 per group). Post-mortem analysis of GR-expressing tumors revealed a threefold increase in apoptotic (TUNEL positive) cells (P<0.01). Infection with the GR-expressing adenovirus caused a significant reduction in Bcl-2 and Bcl-xL transcripts. Furthermore, in both the GR-expressing adenovirus-infected cells and tumors, a significant number of uninfected cells underwent apoptosis, supporting a bystander cell killing effect. Therefore, GR expression is pro-apoptotic for human SCLCs in vivo, as well as in vitro, suggesting that loss of GR confers a survival advantage to SCLCs.
Sommer
Paula
P
School of Biological Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa.
Cowen
Rachel L
RL
Berry
Andrew
A
Cookson
Ann
A
Telfer
Brian A
BA
Williams
Kaye J
KJ
Stratford
Ian J
IJ
Kay
Paul
P
White
Anne
A
Ray
David W
DW
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000502:physiology; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology; D014162:Transfection; D047368:Tumor Burden / Q000235:genetics; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D008164:Luminescent Proteins; D011965:Receptors, Glucocorticoid