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CXCR4 receptor expression and prosta...

Kukreja, Promil.

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CXCR4 receptor expression and prostate cancer bone metastasis: Role of stromal cell derived factor-1 alpha and nuclear factor kappa B.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	CXCR4 receptor expression and prostate cancer bone metastasis: Role of stromal cell derived factor-1 alpha and nuclear factor kappa B./
作者:	Kukreja, Promil.
面頁冊數:	147 p.
附註:	Source: Dissertation Abstracts International, Volume: 67-03, Section: B, page: 1388.
Contained By:	Dissertation Abstracts International67-03B.
標題:	Health Sciences, Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3210877
ISBN:	9780542609008

CXCR4 receptor expression and prostate cancer bone metastasis: Role of stromal cell derived factor-1 alpha and nuclear factor kappa B.
Kukreja, Promil.

CXCR4 receptor expression and prostate cancer bone metastasis: Role of stromal cell derived factor-1 alpha and nuclear factor kappa B. - 147 p.

Source: Dissertation Abstracts International, Volume: 67-03, Section: B, page: 1388.

Thesis (Ph.D.)--Tulane University, 2005.

Prostate cancer (PC) is the second leading cause of cancer-related mortality in adult male population. Majority of PC related mortality and morbidity are dictated by its metastasis to bone. Despite advances in medicine, there is no specific screening, prevention and treatment of the bone metastasis. This calls for better understanding of the molecular mechanisms involved in etiology and progression of PC metastasis to bone. In this present study, we have investigated the molecular mechanisms that may be involved in transmigration of PC cells to the bone marrow. We have used two PC cell lines derived from advanced PC patients, PC-3 cells derived from bone metastasis and, LNCaP cells derived from lymph node metastasis. The chemokine stromal derived factor-1 alpha (SDF-1alpha) and its receptor receptor, CXCR4 play a crucial role in adhesion and trans-endothelial migration (TEM) of prostate cancer (PC) cells. We tested the hypothesis that enhanced expression of CXCR4 in PC cells is dependent upon SDF-1alpha mediated activation of NF-kappaB. SDF-1alpha increased the CXCR4 mRNA and protein expression in PC-3 cells but not in LNCaP cells. Similarly, SDF-1alpha enhanced the NF-kappaB-dependent transcriptional activity in PC-3 cells but not in LNCaP cells. SDF-1alpha increased adhesion of PC-3 cells to the HUVEC monolayer and enhanced TEM, which was abrogated with anti-CXCR4 monoclonal antibody. Suppression of NF-kappaB activity in PC-3 cells by a mutant IKB-alpha super-repressor adenoviral vector decreased the CXCR4 mRNA expression and inhibited the adhesion and TEM. Transient over-expression of p65 subunit of NF-kappaB in PC-3 cells up-regulated CXCR4 receptor expression, and increased the adhesion and TEM of these cells in response to SDF-1alpha gradient. Treatment of PC-3 cells with SDF-1alpha led to nuclear translocation of NF-kappaB protein within 15--30 minutes, which correlated with IkappaBalpha phosphorylation. A p42/44 MAPK (Erk 1/2) biphasic activation pattern was observed in these cells at 15 minutes and 3 hours after SDF-1alpha treatment. Phosphorylation of IKKalpha was observed within 30 minutes, which was blocked by PD98059 (MEK inhibitor). SDF-1alpha induced NF-kappaB reporter activity was also blocked by co-treatment of PC-3 cells with PD98059. PD98059 co-treatment significantly inhibited SDF-1alpha induced CXCR4 receptor expression as shown by flow cytometry and also inhibited SDF-1alpha induced TEM of PC-3 cells in response to a chemokine gradient. These data suggest that SDF-1alpha induced expression of CXCR4 in PC-3 cells is dependent upon MEK-ERK signaling cascade and NF-kappaB activation, and that trans-endothelial migration of PC cells is facilitated by SDF-1alpha, a chemokine present in the bone marrow compartment.

ISBN: 9780542609008Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

CXCR4 receptor expression and prostate cancer bone metastasis: Role of stromal cell derived factor-1 alpha and nuclear factor kappa B.
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520 $a Prostate cancer (PC) is the second leading cause of cancer-related mortality in adult male population. Majority of PC related mortality and morbidity are dictated by its metastasis to bone. Despite advances in medicine, there is no specific screening, prevention and treatment of the bone metastasis. This calls for better understanding of the molecular mechanisms involved in etiology and progression of PC metastasis to bone. In this present study, we have investigated the molecular mechanisms that may be involved in transmigration of PC cells to the bone marrow. We have used two PC cell lines derived from advanced PC patients, PC-3 cells derived from bone metastasis and, LNCaP cells derived from lymph node metastasis. The chemokine stromal derived factor-1 alpha (SDF-1alpha) and its receptor receptor, CXCR4 play a crucial role in adhesion and trans-endothelial migration (TEM) of prostate cancer (PC) cells. We tested the hypothesis that enhanced expression of CXCR4 in PC cells is dependent upon SDF-1alpha mediated activation of NF-kappaB. SDF-1alpha increased the CXCR4 mRNA and protein expression in PC-3 cells but not in LNCaP cells. Similarly, SDF-1alpha enhanced the NF-kappaB-dependent transcriptional activity in PC-3 cells but not in LNCaP cells. SDF-1alpha increased adhesion of PC-3 cells to the HUVEC monolayer and enhanced TEM, which was abrogated with anti-CXCR4 monoclonal antibody. Suppression of NF-kappaB activity in PC-3 cells by a mutant IKB-alpha super-repressor adenoviral vector decreased the CXCR4 mRNA expression and inhibited the adhesion and TEM. Transient over-expression of p65 subunit of NF-kappaB in PC-3 cells up-regulated CXCR4 receptor expression, and increased the adhesion and TEM of these cells in response to SDF-1alpha gradient. Treatment of PC-3 cells with SDF-1alpha led to nuclear translocation of NF-kappaB protein within 15--30 minutes, which correlated with IkappaBalpha phosphorylation. A p42/44 MAPK (Erk 1/2) biphasic activation pattern was observed in these cells at 15 minutes and 3 hours after SDF-1alpha treatment. Phosphorylation of IKKalpha was observed within 30 minutes, which was blocked by PD98059 (MEK inhibitor). SDF-1alpha induced NF-kappaB reporter activity was also blocked by co-treatment of PC-3 cells with PD98059. PD98059 co-treatment significantly inhibited SDF-1alpha induced CXCR4 receptor expression as shown by flow cytometry and also inhibited SDF-1alpha induced TEM of PC-3 cells in response to a chemokine gradient. These data suggest that SDF-1alpha induced expression of CXCR4 in PC-3 cells is dependent upon MEK-ERK signaling cascade and NF-kappaB activation, and that trans-endothelial migration of PC cells is facilitated by SDF-1alpha, a chemokine present in the bone marrow compartment.
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