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Regulation of the cell cycle and PI3K/Akt/mTOR signaling pathway by tanshinone I in human breast cancer cell lines.

Wang L, Wu J, Lu J, Ma R, Sun D, Tang J - Mol Med Rep (2014)

Bottom Line: Tan I exerted similar antiproliferative activities and induction of apoptosis, resulting in S phase arrest accompanied by decreases in cyclin B and increases in cyclin E and cyclin A proteins, which may have been associated with the upregulation of cyclin‑dependent kinase inhibitors p21Cip1 and p27Kip1.In addition, Tan I was found to downregulate anti‑apoptotic and upregulate associated apoptotic components of the PI3K/Akt/mTOR signaling pathway.These results clearly indicated that the mechanism of action of Tan I involved, at least partially, an effect on the PI3K/Akt/mTOR signaling pathway, providing new information for anticancer drug design and development.

View Article: PubMed Central - PubMed

Affiliation: First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210046, P.R. China.

ABSTRACT
Breast cancer is the second leading cause of cancer‑related mortality in females worldwide. Therefore, identifying alternative strategies to combat the disease mortality is important. The aim of the present study was to investigate the effect of tanshinone I (Tan I) on the tumorigenicity of estrogen‑responsive MCF‑7 and estrogen‑independent MDA‑MB‑453 human breast cancer cells. The cytotoxicity of Tan I was evaluated using a Cell Counting Kit‑8 assay, the apoptosis and cell cycle distribution were detected using flow cytometry and the cell morphology was observed using a fluorescence microscope. In addition, the cell cycle regulatory proteins and apoptosis‑associated proteins involved in the phosphatidylinositide 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway were detected using western blot analysis using specific protein antibodies. The MCF‑7 and MDA‑MB‑453 cells were equally sensitive to Tan I regardless of their responsiveness to estrogen. Tan I exerted similar antiproliferative activities and induction of apoptosis, resulting in S phase arrest accompanied by decreases in cyclin B and increases in cyclin E and cyclin A proteins, which may have been associated with the upregulation of cyclin‑dependent kinase inhibitors p21Cip1 and p27Kip1. In addition, Tan I was found to downregulate anti‑apoptotic and upregulate associated apoptotic components of the PI3K/Akt/mTOR signaling pathway. Notably, treatment with the PI3K inhibitor, LY294002, decreased the levels of phosphorylated (p)‑PI3K, p‑Akt and p‑mTOR. These results clearly indicated that the mechanism of action of Tan I involved, at least partially, an effect on the PI3K/Akt/mTOR signaling pathway, providing new information for anticancer drug design and development.

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Related in: MedlinePlus

Cell cycle regulatory proteins in breast cancer cells following treatment with Tan I for 48 h. (A) MCF-7 cells and (B) MDA-MB-453 cells. Tan I, tanshinone I; Cdk2, cyclin-dependent kinase.
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f6-mmr-11-02-0931: Cell cycle regulatory proteins in breast cancer cells following treatment with Tan I for 48 h. (A) MCF-7 cells and (B) MDA-MB-453 cells. Tan I, tanshinone I; Cdk2, cyclin-dependent kinase.

Mentions: Following treatment of the MCF-7 cells for 48 h, Tan I increased the expression of cyclin E and cyclin A, an indicator for cell entry into the S phase, and decreased cyclin B in a dose-dependent manner (Fig. 6). Since the activities of Cdk2 are essential for the facilitation of S phase entry and progression and are opposed by the Cip/Kip family, including p21Cip1 and p27Kip1, the effects of Tan I on the expression of Cdk and the Cdk inhibitors p21Cip1 and p27Kip1 were examined. As shown in Fig. 6A, the abundance of Cdk2 was marginally reduced in the MCF-7 cells exposed to Tan I compared with the control, whereas the protein levels of p21Cip1 and p27Kip1 in the MCF-1 cells increased dose-dependently in response to Tan I. Subsequently, the present study examined the effects of Tan I on the cell cycle regulatory proteins in the MDA-MB-453 cells, observed after 48 h treatment with 2.5 or 5 μg/ml Tan I. A similar pattern of results were observed in the MDA-MB-453 cells (Fig. 6B). These results implied that Tan I inhibited cell cycle progression by decreasing cyclin B and Cdk2 proteins and increasing cyclin E and cyclin A proteins, which may be associated with the upregulation of CDK inhibitors p21Cip1 and p27Kip1 in the MCF-7 and MDA-MB-453 cells.


Regulation of the cell cycle and PI3K/Akt/mTOR signaling pathway by tanshinone I in human breast cancer cell lines.

Wang L, Wu J, Lu J, Ma R, Sun D, Tang J - Mol Med Rep (2014)

Cell cycle regulatory proteins in breast cancer cells following treatment with Tan I for 48 h. (A) MCF-7 cells and (B) MDA-MB-453 cells. Tan I, tanshinone I; Cdk2, cyclin-dependent kinase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4262478&req=5

f6-mmr-11-02-0931: Cell cycle regulatory proteins in breast cancer cells following treatment with Tan I for 48 h. (A) MCF-7 cells and (B) MDA-MB-453 cells. Tan I, tanshinone I; Cdk2, cyclin-dependent kinase.
Mentions: Following treatment of the MCF-7 cells for 48 h, Tan I increased the expression of cyclin E and cyclin A, an indicator for cell entry into the S phase, and decreased cyclin B in a dose-dependent manner (Fig. 6). Since the activities of Cdk2 are essential for the facilitation of S phase entry and progression and are opposed by the Cip/Kip family, including p21Cip1 and p27Kip1, the effects of Tan I on the expression of Cdk and the Cdk inhibitors p21Cip1 and p27Kip1 were examined. As shown in Fig. 6A, the abundance of Cdk2 was marginally reduced in the MCF-7 cells exposed to Tan I compared with the control, whereas the protein levels of p21Cip1 and p27Kip1 in the MCF-1 cells increased dose-dependently in response to Tan I. Subsequently, the present study examined the effects of Tan I on the cell cycle regulatory proteins in the MDA-MB-453 cells, observed after 48 h treatment with 2.5 or 5 μg/ml Tan I. A similar pattern of results were observed in the MDA-MB-453 cells (Fig. 6B). These results implied that Tan I inhibited cell cycle progression by decreasing cyclin B and Cdk2 proteins and increasing cyclin E and cyclin A proteins, which may be associated with the upregulation of CDK inhibitors p21Cip1 and p27Kip1 in the MCF-7 and MDA-MB-453 cells.

Bottom Line: Tan I exerted similar antiproliferative activities and induction of apoptosis, resulting in S phase arrest accompanied by decreases in cyclin B and increases in cyclin E and cyclin A proteins, which may have been associated with the upregulation of cyclin‑dependent kinase inhibitors p21Cip1 and p27Kip1.In addition, Tan I was found to downregulate anti‑apoptotic and upregulate associated apoptotic components of the PI3K/Akt/mTOR signaling pathway.These results clearly indicated that the mechanism of action of Tan I involved, at least partially, an effect on the PI3K/Akt/mTOR signaling pathway, providing new information for anticancer drug design and development.

View Article: PubMed Central - PubMed

Affiliation: First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210046, P.R. China.

ABSTRACT
Breast cancer is the second leading cause of cancer‑related mortality in females worldwide. Therefore, identifying alternative strategies to combat the disease mortality is important. The aim of the present study was to investigate the effect of tanshinone I (Tan I) on the tumorigenicity of estrogen‑responsive MCF‑7 and estrogen‑independent MDA‑MB‑453 human breast cancer cells. The cytotoxicity of Tan I was evaluated using a Cell Counting Kit‑8 assay, the apoptosis and cell cycle distribution were detected using flow cytometry and the cell morphology was observed using a fluorescence microscope. In addition, the cell cycle regulatory proteins and apoptosis‑associated proteins involved in the phosphatidylinositide 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway were detected using western blot analysis using specific protein antibodies. The MCF‑7 and MDA‑MB‑453 cells were equally sensitive to Tan I regardless of their responsiveness to estrogen. Tan I exerted similar antiproliferative activities and induction of apoptosis, resulting in S phase arrest accompanied by decreases in cyclin B and increases in cyclin E and cyclin A proteins, which may have been associated with the upregulation of cyclin‑dependent kinase inhibitors p21Cip1 and p27Kip1. In addition, Tan I was found to downregulate anti‑apoptotic and upregulate associated apoptotic components of the PI3K/Akt/mTOR signaling pathway. Notably, treatment with the PI3K inhibitor, LY294002, decreased the levels of phosphorylated (p)‑PI3K, p‑Akt and p‑mTOR. These results clearly indicated that the mechanism of action of Tan I involved, at least partially, an effect on the PI3K/Akt/mTOR signaling pathway, providing new information for anticancer drug design and development.

Show MeSH
Related in: MedlinePlus