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Resveratrol chemosensitizes HER-2-overexpressing breast cancer cells to docetaxel chemoresistance by inhibiting docetaxel-mediated activation of HER-2 – Akt axis

View Article: PubMed Central - PubMed

ABSTRACT

As breast cancer cells often develop chemoresistance, better therapeutic options are in search to circumvent it. Here we demonstrate that human epidermal growth factor receptor-2 (HER-2)-overexpressing breast cancer cells resist docetaxel-induced cytotoxicity by upregulating HER-2 and its activity downstream, through Akt and mitogen-activated protein kinase (MAPK) pathways. We observed that introducing resveratrol as a chemosensitizer in docetaxel chemotherapy blocks upregulation and activation of HER-2 in addition to blocking downstream signaling pathways such as Akt. Resveratrol and docetaxel combination results in the synergistic induction of cell death in HER-2-overexpressing SK-BR-3 cells, whereas introduction of wild-type HER-2 in MDA-MD-231 cells increased the resistance to docetaxel. Dominant-negative HER-2 sensitizes SK-BR-3 cells to docetaxel. Our study identified a new synergistic therapeutic combination that targets HER-2-induced breast cancer resistance and might help to overcome therapeutic resistance during breast cancer therapy. The synergism of docetaxel and resveratrol was maximum in SK-BR-3, which is unique among the cell lines studied, due to its high expression status of HER-2, a receptor known to dictate the signaling environment of breast cancer cells. Docetaxel could further induce HER-2 activity in these cells, which was downregulated on resveratrol treatment. Transfection of DN-HER-2 in SK-BR-3 cells inhibits the synergism as the transfection itself sensitizes these cells to docetaxel, leaving no role for resveratrol, whereas ectopic expression of HER-2 introduces the synergism in MDA-MB-231, the triple-negative cell line, in which the synergism was minimum, attesting the crucial role of HER-2 in suppressing the sensitivity to docetaxel. Single-agent docetaxel induced HER-2-mediated resistance to cell death, which was blocked by resveratrol. Resveratrol also downregulated docetaxel-induced activation of MAPK and Akt, survival signaling pathways downstream of HER-2. In short, this study, for the first time, establishes the role of HER-2–Akt signaling axis in regulating the synergistic effect of docetaxel and resveratrol in breast cancer cells overexpressing HER-2.

No MeSH data available.


Related in: MedlinePlus

Proposed model for the synergistic effect of docetaxel and resveratrol. Resveratrol downregulates docetaxel-induced upregulation of HER-2, Akt and MAPKs, while that of NF-κB is unaffected. The study postulates that docetaxel-induced upregulation of HER-2–Akt signaling and the downregulation of the same by resveratrol is the main mechanism governing the synergistic effect of docetaxel and resveratrol in HER-2-overexpressing breast cancer cells. Although MAPK pathway does not regulate the synergism, it is getting activated by docetaxel and downregulated by resveratrol. The bold lines indicate the signaling pathways regulating the synergism, whereas the dotted lines represent those that do not have any role in the same.
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fig6: Proposed model for the synergistic effect of docetaxel and resveratrol. Resveratrol downregulates docetaxel-induced upregulation of HER-2, Akt and MAPKs, while that of NF-κB is unaffected. The study postulates that docetaxel-induced upregulation of HER-2–Akt signaling and the downregulation of the same by resveratrol is the main mechanism governing the synergistic effect of docetaxel and resveratrol in HER-2-overexpressing breast cancer cells. Although MAPK pathway does not regulate the synergism, it is getting activated by docetaxel and downregulated by resveratrol. The bold lines indicate the signaling pathways regulating the synergism, whereas the dotted lines represent those that do not have any role in the same.

Mentions: The response of Akt to docetaxel and resveratrol was also reflected in the expression pattern of the downstream signaling molecules. Resveratrol downregulated docetaxel-induced overexpression of survivin, a pro-survival protein, extensively regulated by Akt24 (Figure 5e). Although XIAP is generally considered as an NF-κB-dependent gene, it has been shown to be a major target of Akt at post-mitochondrial level.25 We found that docetaxel-induced activation of XIAP is downregulated by resveratrol (Figure 5f). Another survival signal, which gets activated in response to the activation of PI3K/Akt pathway is Bcl-2 (Asnaghi, 2004). We observed a time-dependant upregulation of Bcl-2 by docetaxel, which was clearly downregulated by pretreatment with resveratrol (Figure 5g). Taken together, these results demonstrate the efficacy of resveratrol in overcoming docetaxel-induced HER-2 activation and its downstream survival signal Akt, which is pivotal in resveratrol-induced chemosensitization of breast cancer cells to docetaxel. Figure 6 illustrates our findings in a nutshell.


Resveratrol chemosensitizes HER-2-overexpressing breast cancer cells to docetaxel chemoresistance by inhibiting docetaxel-mediated activation of HER-2 – Akt axis
Proposed model for the synergistic effect of docetaxel and resveratrol. Resveratrol downregulates docetaxel-induced upregulation of HER-2, Akt and MAPKs, while that of NF-κB is unaffected. The study postulates that docetaxel-induced upregulation of HER-2–Akt signaling and the downregulation of the same by resveratrol is the main mechanism governing the synergistic effect of docetaxel and resveratrol in HER-2-overexpressing breast cancer cells. Although MAPK pathway does not regulate the synergism, it is getting activated by docetaxel and downregulated by resveratrol. The bold lines indicate the signaling pathways regulating the synergism, whereas the dotted lines represent those that do not have any role in the same.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4979566&req=5

fig6: Proposed model for the synergistic effect of docetaxel and resveratrol. Resveratrol downregulates docetaxel-induced upregulation of HER-2, Akt and MAPKs, while that of NF-κB is unaffected. The study postulates that docetaxel-induced upregulation of HER-2–Akt signaling and the downregulation of the same by resveratrol is the main mechanism governing the synergistic effect of docetaxel and resveratrol in HER-2-overexpressing breast cancer cells. Although MAPK pathway does not regulate the synergism, it is getting activated by docetaxel and downregulated by resveratrol. The bold lines indicate the signaling pathways regulating the synergism, whereas the dotted lines represent those that do not have any role in the same.
Mentions: The response of Akt to docetaxel and resveratrol was also reflected in the expression pattern of the downstream signaling molecules. Resveratrol downregulated docetaxel-induced overexpression of survivin, a pro-survival protein, extensively regulated by Akt24 (Figure 5e). Although XIAP is generally considered as an NF-κB-dependent gene, it has been shown to be a major target of Akt at post-mitochondrial level.25 We found that docetaxel-induced activation of XIAP is downregulated by resveratrol (Figure 5f). Another survival signal, which gets activated in response to the activation of PI3K/Akt pathway is Bcl-2 (Asnaghi, 2004). We observed a time-dependant upregulation of Bcl-2 by docetaxel, which was clearly downregulated by pretreatment with resveratrol (Figure 5g). Taken together, these results demonstrate the efficacy of resveratrol in overcoming docetaxel-induced HER-2 activation and its downstream survival signal Akt, which is pivotal in resveratrol-induced chemosensitization of breast cancer cells to docetaxel. Figure 6 illustrates our findings in a nutshell.

View Article: PubMed Central - PubMed

ABSTRACT

As breast cancer cells often develop chemoresistance, better therapeutic options are in search to circumvent it. Here we demonstrate that human epidermal growth factor receptor-2 (HER-2)-overexpressing breast cancer cells resist docetaxel-induced cytotoxicity by upregulating HER-2 and its activity downstream, through Akt and mitogen-activated protein kinase (MAPK) pathways. We observed that introducing resveratrol as a chemosensitizer in docetaxel chemotherapy blocks upregulation and activation of HER-2 in addition to blocking downstream signaling pathways such as Akt. Resveratrol and docetaxel combination results in the synergistic induction of cell death in HER-2-overexpressing SK-BR-3 cells, whereas introduction of wild-type HER-2 in MDA-MD-231 cells increased the resistance to docetaxel. Dominant-negative HER-2 sensitizes SK-BR-3 cells to docetaxel. Our study identified a new synergistic therapeutic combination that targets HER-2-induced breast cancer resistance and might help to overcome therapeutic resistance during breast cancer therapy. The synergism of docetaxel and resveratrol was maximum in SK-BR-3, which is unique among the cell lines studied, due to its high expression status of HER-2, a receptor known to dictate the signaling environment of breast cancer cells. Docetaxel could further induce HER-2 activity in these cells, which was downregulated on resveratrol treatment. Transfection of DN-HER-2 in SK-BR-3 cells inhibits the synergism as the transfection itself sensitizes these cells to docetaxel, leaving no role for resveratrol, whereas ectopic expression of HER-2 introduces the synergism in MDA-MB-231, the triple-negative cell line, in which the synergism was minimum, attesting the crucial role of HER-2 in suppressing the sensitivity to docetaxel. Single-agent docetaxel induced HER-2-mediated resistance to cell death, which was blocked by resveratrol. Resveratrol also downregulated docetaxel-induced activation of MAPK and Akt, survival signaling pathways downstream of HER-2. In short, this study, for the first time, establishes the role of HER-2–Akt signaling axis in regulating the synergistic effect of docetaxel and resveratrol in breast cancer cells overexpressing HER-2.

No MeSH data available.


Related in: MedlinePlus