Abstract
Constitutive activation of nuclear factor-κB (NF-κB) has been directly implicated in tumorigenesis of various cancer types, including melanoma. Inhibitor of κB kinase (IKK) functions as a major mediator of NF-κB activation. Thus, development of an IKK-specific inhibitor has been a high priority, although it remains unclear whether systemic inhibition of IKK will provide therapeutic benefit. In this study, we show that inhibition of NF-κB activity in melanocytes that are persistently expressing an active H-RasV12 gene and are deficient in the tumor suppressors inhibitor A of cyclin-dependent kinase 4/alternative reading frame results in reduction of melanoma tumor growth in vivo. This effect is, at least in part, via regulation of NF-κB nuclear activation and RelA phosphorylation. Based on this result, we developed a double hammerhead ribozyme long-term expression system to silence either IKKα or IKKβ. The ribozymes were placed in an EBV construct and delivered i.v. to nude mice bearing melanoma lesions, which developed after i.v. injection of H-Ras-transformed melanoma cells. Our in vivo data show that knockdown of endogenous IKKβ significantly reduces the growth of the melanoma lesions and knockdown of either IKKα or IKKβ prolongs the life span of immunocompetent mice.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3127-3134 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 67 |
| Issue number | 7 |
| DOIs | |
| State | Published - Apr 1 2007 |
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All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
Cite this
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Systemic targeting inhibitor of κB kinase inhibits melanoma tumor growth. / Yang, Jinming; Pan, Wei Hua; Clawson, Gary A.; Richmond, Ann.
In: Cancer Research, Vol. 67, No. 7, 01.04.2007, p. 3127-3134.Research output: Contribution to journal › Article
TY - JOUR
T1 - Systemic targeting inhibitor of κB kinase inhibits melanoma tumor growth
AU - Yang, Jinming
AU - Pan, Wei Hua
AU - Clawson, Gary A.
AU - Richmond, Ann
PY - 2007/4/1
Y1 - 2007/4/1
N2 - Constitutive activation of nuclear factor-κB (NF-κB) has been directly implicated in tumorigenesis of various cancer types, including melanoma. Inhibitor of κB kinase (IKK) functions as a major mediator of NF-κB activation. Thus, development of an IKK-specific inhibitor has been a high priority, although it remains unclear whether systemic inhibition of IKK will provide therapeutic benefit. In this study, we show that inhibition of NF-κB activity in melanocytes that are persistently expressing an active H-RasV12 gene and are deficient in the tumor suppressors inhibitor A of cyclin-dependent kinase 4/alternative reading frame results in reduction of melanoma tumor growth in vivo. This effect is, at least in part, via regulation of NF-κB nuclear activation and RelA phosphorylation. Based on this result, we developed a double hammerhead ribozyme long-term expression system to silence either IKKα or IKKβ. The ribozymes were placed in an EBV construct and delivered i.v. to nude mice bearing melanoma lesions, which developed after i.v. injection of H-Ras-transformed melanoma cells. Our in vivo data show that knockdown of endogenous IKKβ significantly reduces the growth of the melanoma lesions and knockdown of either IKKα or IKKβ prolongs the life span of immunocompetent mice.
AB - Constitutive activation of nuclear factor-κB (NF-κB) has been directly implicated in tumorigenesis of various cancer types, including melanoma. Inhibitor of κB kinase (IKK) functions as a major mediator of NF-κB activation. Thus, development of an IKK-specific inhibitor has been a high priority, although it remains unclear whether systemic inhibition of IKK will provide therapeutic benefit. In this study, we show that inhibition of NF-κB activity in melanocytes that are persistently expressing an active H-RasV12 gene and are deficient in the tumor suppressors inhibitor A of cyclin-dependent kinase 4/alternative reading frame results in reduction of melanoma tumor growth in vivo. This effect is, at least in part, via regulation of NF-κB nuclear activation and RelA phosphorylation. Based on this result, we developed a double hammerhead ribozyme long-term expression system to silence either IKKα or IKKβ. The ribozymes were placed in an EBV construct and delivered i.v. to nude mice bearing melanoma lesions, which developed after i.v. injection of H-Ras-transformed melanoma cells. Our in vivo data show that knockdown of endogenous IKKβ significantly reduces the growth of the melanoma lesions and knockdown of either IKKα or IKKβ prolongs the life span of immunocompetent mice.
UR - http://www.scopus.com/inward/record.url?scp=34248178207&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34248178207&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-06-3547
DO - 10.1158/0008-5472.CAN-06-3547
M3 - Article
C2 - 17409419
AN - SCOPUS:34248178207
VL - 67
SP - 3127
EP - 3134
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 7
ER -