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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.

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IKK activity is necessary for doxorubicin to increase Myc, cyclin D1 and twist protein levels in MCF7 cells. The cells (A) MCF/IKKα-WT, (B) MCF/IKKα-KD, (C) MCF/IKKβ-WT, and (D) MCF/IKKβ-KD were treated with 200 nM doxorubicin for 3hours, and then were released with complete medium for further 24 hours. The cytoplasmic and nuclear extracts were subjected to Western blot analysis.
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Figure 7: IKK activity is necessary for doxorubicin to increase Myc, cyclin D1 and twist protein levels in MCF7 cells. The cells (A) MCF/IKKα-WT, (B) MCF/IKKα-KD, (C) MCF/IKKβ-WT, and (D) MCF/IKKβ-KD were treated with 200 nM doxorubicin for 3hours, and then were released with complete medium for further 24 hours. The cytoplasmic and nuclear extracts were subjected to Western blot analysis.

Mentions: Because cyclin D1 and Twist proteins were increased in MCF7 cells following a 3-hour doxorubicin exposure, we characterized whether the tumorigenic and invasive ability of MCF7 cells was subsequently enhanced. Indeed, the cells released from a 3-hour doxorubicin treatment increased their ability to grow in soft-agar and to pass through matrigel. Co-treatment with Bay11-0782 partially suppressed these activities, and re-addition of Bay11-0782 after released from doxorubicin markedly decreased these activities to lower than the levels of the untreated control (Figure 6C and 6D). These results were further supported by analyzing the effect of doxorubicin on IKK-transfected cells. Following the same treatments as above, the protein levels of Myc, cyclin D1, and Twist were increased in wild-type IKKα- and IKKβ-transfected cells (Figure 7A and 7C), but were not changed in kinase-dead IKKα- and IKKβ-transfected cells (Figure 7B and 7D).


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

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

IKK activity is necessary for doxorubicin to increase Myc, cyclin D1 and twist protein levels in MCF7 cells. The cells (A) MCF/IKKα-WT, (B) MCF/IKKα-KD, (C) MCF/IKKβ-WT, and (D) MCF/IKKβ-KD were treated with 200 nM doxorubicin for 3hours, and then were released with complete medium for further 24 hours. The cytoplasmic and nuclear extracts were subjected to Western blot analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: IKK activity is necessary for doxorubicin to increase Myc, cyclin D1 and twist protein levels in MCF7 cells. The cells (A) MCF/IKKα-WT, (B) MCF/IKKα-KD, (C) MCF/IKKβ-WT, and (D) MCF/IKKβ-KD were treated with 200 nM doxorubicin for 3hours, and then were released with complete medium for further 24 hours. The cytoplasmic and nuclear extracts were subjected to Western blot analysis.
Mentions: Because cyclin D1 and Twist proteins were increased in MCF7 cells following a 3-hour doxorubicin exposure, we characterized whether the tumorigenic and invasive ability of MCF7 cells was subsequently enhanced. Indeed, the cells released from a 3-hour doxorubicin treatment increased their ability to grow in soft-agar and to pass through matrigel. Co-treatment with Bay11-0782 partially suppressed these activities, and re-addition of Bay11-0782 after released from doxorubicin markedly decreased these activities to lower than the levels of the untreated control (Figure 6C and 6D). These results were further supported by analyzing the effect of doxorubicin on IKK-transfected cells. Following the same treatments as above, the protein levels of Myc, cyclin D1, and Twist were increased in wild-type IKKα- and IKKβ-transfected cells (Figure 7A and 7C), but were not changed in kinase-dead IKKα- and IKKβ-transfected cells (Figure 7B and 7D).

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