Selective cancer targeting via aberrant behavior of cancer cell-associated glucocorticoid receptor.
Glucocorticoid receptors (GRs) are ubiquitous, nuclear hormone receptors residing in cell types of both cancer and noncancerous origin. It is not known whether cancer cell-associated GR alone can be selectively manipulated for delivery of exogenous genes to its nucleus for eliciting anticancer effect. We find that GR ligand, dexamethasone (Dex) in association with cationic lipoplex (termed as targeted lipoplex) could selectively manipulate GR in cancer cells alone for the delivery of transgenes in the nucleus, a phenomenon that remained unobserved in normal cells. The targeted lipoplex (i) showed GR-targeted transfections in all cancer cells experimented (P < 0.01), (ii) significantly diminished transfection in cancer cells when GR is downregulated (P < 0.01), and (iii) elicited specific nuclear translocation of targeted lipoplex in cancer cells, followed by upregulated transactivation of glucocorticoid response element (GRE)- promoted gene. Using anticancer gene, targeted lipoplex induced significant tumor growth retardation in mice in comparison to different control groups (P < 0.05). Interestingly, cell surface-associated Hsp90 in cancer cells assisted the intracellular uptake of GR-targeted lipoplex. Moreover, selective inhibition of Hsp90 in noncancer cells resulted in cancer cell-like, aberrant, GR activation. The current study discovers a therapeutically important, unique property of cancer cell associated-GR that may be linked to a compromised role of Hsp90.Molecular Therapy (2009) 17 4, 623-631 doi:10.1038/mt.2009.4.
Mukherjee
Amarnath
A
Division of Lipid Science and Technology, Indian Institute of Chemical Technology, Hyderabad, India.
Narayan
Kumar P
KP
Pal
Krishnendu
K
Kumar
Jerald M
JM
Rangaraj
Nandini
N
Kalivendi
Shasi V
SV
Banerjee
Rajkumar
R
D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D014162:Transfection; D019076:Transgenes
D018841:HSP90 Heat-Shock Proteins; D011965:Receptors, Glucocorticoid