Limits...
IκB kinases increase Myc protein stability and enhance progression of breast cancer cells.

Yeh PY, Lu YS, Ou DL, Cheng AL - Mol. Cancer (2011)

Bottom Line: Consequently, these treatments decrease the tumorigenic and invasive ability of breast cancer cells.Inhibition of IKKs prevents these doxorubicin-induced effects.Our study indicates that IKKs tightly regulate Myc expression through prolonging protein stability, and suggests that IKKs are potentially therapeutic targets and that suppression of IKKs may be used following chemotherapy to reduce the risk of treatment-induced tumor progression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology, National Taiwan University Hospital, No, 7, Chung-Shan South Road, Taipei, 100, Taiwan.

ABSTRACT

Background: Both IκB kinase (IKK) complex and oncgenic protein Myc play important roles in cancer progression, including cancer cell invasiveness and metastasis. The levels of Myc is regulated by the phosphorylation of Myc at Thr58 and Ser62.

Results: In this study, we show that the expression of Myc is associated with IKKα and IKKβ in breast cancers and that Myc is an IKKs substrate. Suppression of IKK activity by either chemical inhibitor or transfection of kinase-dead mutants decreases the phosphorylation of Myc at Ser62 and enhances the degradation of Myc. Consequently, these treatments decrease the tumorigenic and invasive ability of breast cancer cells. Furthermore, doxorubicin, a frequently used anticancer drug in breast cancer, activates IKKs and Myc, thereby increasing invasiveness and tumorigenesis of breast carcinoma MCF7 cells. Inhibition of IKKs prevents these doxorubicin-induced effects.

Conclusions: Our study indicates that IKKs tightly regulate Myc expression through prolonging protein stability, and suggests that IKKs are potentially therapeutic targets and that suppression of IKKs may be used following chemotherapy to reduce the risk of treatment-induced tumor progression.

Show MeSH

Related in: MedlinePlus

Myc expression level is associated with IKKα and IKKβ but not NF-κB. IHC staining was used to identify the expression of IKKα, IKKβ, NF-κB p65 and Myc in breast cancer specimens (upper panel). Representative pictures of positive and negative staining are shown. Statistic analysis shows a positive association among IKKα and/or IKKβ and Myc expression in 21 breast cancer specimens (lower panel).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3104363&req=5

Figure 1: Myc expression level is associated with IKKα and IKKβ but not NF-κB. IHC staining was used to identify the expression of IKKα, IKKβ, NF-κB p65 and Myc in breast cancer specimens (upper panel). Representative pictures of positive and negative staining are shown. Statistic analysis shows a positive association among IKKα and/or IKKβ and Myc expression in 21 breast cancer specimens (lower panel).

Mentions: To identify whether the expression of Myc was associated with IKKs/NF-κB expressions in vivo, IHC staining was used to identify the expression of IKKα, IKKβ, Myc and NF-κB p65 in a total of 21 breast cancer specimens. The staining of more than 50% of the cells in a single field of view and at least 5 fields in a specimen were designated as positive [Figure 1]. The ratio of positive staining was 67% (14/21) for IKKα, 57% (12/21) for IKKβ, 67% (14/21) for NF-κB p65, and 62% (13/21) for Myc. When the expression of Myc was assessed based on nuclear staining, the ratio was 48% (10/21), similar to the result of a previous study [30]. Statistical analysis showed that Myc expression was correlated with IKKα and IKKβ expression, whereas it had no correlation with the expression of NF-κB p65 (Figure 1). This result suggested that IKKs might regulate Myc expression through an NF-κB-independent pathway.


IκB kinases increase Myc protein stability and enhance progression of breast cancer cells.

Yeh PY, Lu YS, Ou DL, Cheng AL - Mol. Cancer (2011)

Myc expression level is associated with IKKα and IKKβ but not NF-κB. IHC staining was used to identify the expression of IKKα, IKKβ, NF-κB p65 and Myc in breast cancer specimens (upper panel). Representative pictures of positive and negative staining are shown. Statistic analysis shows a positive association among IKKα and/or IKKβ and Myc expression in 21 breast cancer specimens (lower panel).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3104363&req=5

Figure 1: Myc expression level is associated with IKKα and IKKβ but not NF-κB. IHC staining was used to identify the expression of IKKα, IKKβ, NF-κB p65 and Myc in breast cancer specimens (upper panel). Representative pictures of positive and negative staining are shown. Statistic analysis shows a positive association among IKKα and/or IKKβ and Myc expression in 21 breast cancer specimens (lower panel).
Mentions: To identify whether the expression of Myc was associated with IKKs/NF-κB expressions in vivo, IHC staining was used to identify the expression of IKKα, IKKβ, Myc and NF-κB p65 in a total of 21 breast cancer specimens. The staining of more than 50% of the cells in a single field of view and at least 5 fields in a specimen were designated as positive [Figure 1]. The ratio of positive staining was 67% (14/21) for IKKα, 57% (12/21) for IKKβ, 67% (14/21) for NF-κB p65, and 62% (13/21) for Myc. When the expression of Myc was assessed based on nuclear staining, the ratio was 48% (10/21), similar to the result of a previous study [30]. Statistical analysis showed that Myc expression was correlated with IKKα and IKKβ expression, whereas it had no correlation with the expression of NF-κB p65 (Figure 1). This result suggested that IKKs might regulate Myc expression through an NF-κB-independent pathway.

Bottom Line: Consequently, these treatments decrease the tumorigenic and invasive ability of breast cancer cells.Inhibition of IKKs prevents these doxorubicin-induced effects.Our study indicates that IKKs tightly regulate Myc expression through prolonging protein stability, and suggests that IKKs are potentially therapeutic targets and that suppression of IKKs may be used following chemotherapy to reduce the risk of treatment-induced tumor progression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology, National Taiwan University Hospital, No, 7, Chung-Shan South Road, Taipei, 100, Taiwan.

ABSTRACT

Background: Both IκB kinase (IKK) complex and oncgenic protein Myc play important roles in cancer progression, including cancer cell invasiveness and metastasis. The levels of Myc is regulated by the phosphorylation of Myc at Thr58 and Ser62.

Results: In this study, we show that the expression of Myc is associated with IKKα and IKKβ in breast cancers and that Myc is an IKKs substrate. Suppression of IKK activity by either chemical inhibitor or transfection of kinase-dead mutants decreases the phosphorylation of Myc at Ser62 and enhances the degradation of Myc. Consequently, these treatments decrease the tumorigenic and invasive ability of breast cancer cells. Furthermore, doxorubicin, a frequently used anticancer drug in breast cancer, activates IKKs and Myc, thereby increasing invasiveness and tumorigenesis of breast carcinoma MCF7 cells. Inhibition of IKKs prevents these doxorubicin-induced effects.

Conclusions: Our study indicates that IKKs tightly regulate Myc expression through prolonging protein stability, and suggests that IKKs are potentially therapeutic targets and that suppression of IKKs may be used following chemotherapy to reduce the risk of treatment-induced tumor progression.

Show MeSH
Related in: MedlinePlus