Selective cancer targeting via aberrant behavior of cancer cell-associated glucocorticoid receptor

Amarnath Mukherjee, Kumar P. Narayan, Krishnendu Pal, Jerald M. Kumar, Nandini Rangaraj, Shasi V. Kalivendi, Rajkumar Banerjee

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)623-631
Number of pages9
JournalMolecular Therapy
Volume17
Issue number4
DOIs
StatePublished - 2009
Externally publishedYes

Fingerprint

Glucocorticoid Receptors
Neoplasms
Transfection
Genes
Response Elements
Cytoplasmic and Nuclear Receptors
Transgenes
Dexamethasone
Transcriptional Activation
Glucocorticoids
Down-Regulation
Ligands

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Mukherjee, A., Narayan, K. P., Pal, K., Kumar, J. M., Rangaraj, N., Kalivendi, S. V., & Banerjee, R. (2009). Selective cancer targeting via aberrant behavior of cancer cell-associated glucocorticoid receptor. Molecular Therapy, 17(4), 623-631. https://doi.org/10.1038/mt.2009.4

Selective cancer targeting via aberrant behavior of cancer cell-associated glucocorticoid receptor. / Mukherjee, Amarnath; Narayan, Kumar P.; Pal, Krishnendu; Kumar, Jerald M.; Rangaraj, Nandini; Kalivendi, Shasi V.; Banerjee, Rajkumar.

In: Molecular Therapy, Vol. 17, No. 4, 2009, p. 623-631.

Research output: Contribution to journalArticle

Mukherjee, A, Narayan, KP, Pal, K, Kumar, JM, Rangaraj, N, Kalivendi, SV & Banerjee, R 2009, 'Selective cancer targeting via aberrant behavior of cancer cell-associated glucocorticoid receptor', Molecular Therapy, vol. 17, no. 4, pp. 623-631. https://doi.org/10.1038/mt.2009.4
Mukherjee, Amarnath ; Narayan, Kumar P. ; Pal, Krishnendu ; Kumar, Jerald M. ; Rangaraj, Nandini ; Kalivendi, Shasi V. ; Banerjee, Rajkumar. / Selective cancer targeting via aberrant behavior of cancer cell-associated glucocorticoid receptor. In: Molecular Therapy. 2009 ; Vol. 17, No. 4. pp. 623-631.
@article{617503b61ee04c5c8c250cdcc839c749,
title = "Selective cancer targeting via aberrant behavior of cancer cell-associated glucocorticoid receptor",
abstract = "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.",
author = "Amarnath Mukherjee and Narayan, {Kumar P.} and Krishnendu Pal and Kumar, {Jerald M.} and Nandini Rangaraj and Kalivendi, {Shasi V.} and Rajkumar Banerjee",
year = "2009",
doi = "10.1038/mt.2009.4",
language = "English (US)",
volume = "17",
pages = "623--631",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - Selective cancer targeting via aberrant behavior of cancer cell-associated glucocorticoid receptor

AU - Mukherjee, Amarnath

AU - Narayan, Kumar P.

AU - Pal, Krishnendu

AU - Kumar, Jerald M.

AU - Rangaraj, Nandini

AU - Kalivendi, Shasi V.

AU - Banerjee, Rajkumar

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=64049106699&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=64049106699&partnerID=8YFLogxK

U2 - 10.1038/mt.2009.4

DO - 10.1038/mt.2009.4

M3 - Article

VL - 17

SP - 623

EP - 631

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 4

ER -