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Curcumol Inhibits Growth and Induces Apoptosis of Colorectal Cancer LoVo Cell Line via IGF-1R and p38 MAPK Pathway.

Wang J, Huang F, Bai Z, Chi B, Wu J, Chen X - Int J Mol Sci (2015)

Bottom Line: Though many researchers have reported curcumol and its bioactivity, the potential molecular mechanism for its anti-cancer effect in colorectal cancer LoVo cells still remains unclear.In the present study, we found that curcumol showed growth inhibition and induced apoptosis of LoVo cells in a dose- and time-dependent manner.The occurrence of its proliferation inhibition and apoptosis came with suppression of IGF-1R expression, and then increased the phosphorylation of p38 mitogen activated protein kinase (MAPK), which might result in a cascade response by inhibiting the CREB survival pathway and finally triggered Bax/Bcl-2 and poly(ADP-ribose) polymerase 1 (PARP-1) apoptosis signals.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Guilin Medical University, Guilin 541004, China. wujiacaiwjc@hotmail.com.

ABSTRACT
Curcumol, isolated from the traditional medical plant Rhizoma Curcumae, is the bioactive component of Zedoary oil, whose potential anti-tumor effect has attracted considerable attention in recent years. Though many researchers have reported curcumol and its bioactivity, the potential molecular mechanism for its anti-cancer effect in colorectal cancer LoVo cells still remains unclear. In the present study, we found that curcumol showed growth inhibition and induced apoptosis of LoVo cells in a dose- and time-dependent manner. The occurrence of its proliferation inhibition and apoptosis came with suppression of IGF-1R expression, and then increased the phosphorylation of p38 mitogen activated protein kinase (MAPK), which might result in a cascade response by inhibiting the CREB survival pathway and finally triggered Bax/Bcl-2 and poly(ADP-ribose) polymerase 1 (PARP-1) apoptosis signals. Moreover, curcumol inhibited colorectal cancer in xenograft models of nude mice. Immunohistochemical and Western blot analysis revealed that curcumol could decrease the expression of ki-67, Bcl-2 as well as CREB1, and increase the expression of Bax and the phosphorylation of p38, which were consistent with our in vitro study. Overall, our in vitro and in vivo data confirmed the anti-cancer activity of curcumol, which was related to a significant inhibition of IGF-1R and activation of p38 MAPKs, indicating that curcumol may be a potential anti-tumor agent for colorectal carcinoma therapy.

No MeSH data available.


Related in: MedlinePlus

Involvement of p38 MAPK pathway in the anti-tumor effect of curcumol. (a,c) Cells were treated with curcumol (0, 0.05, 0.1, 0.2 and 0.4 μΜ/mL) for 48 h, and the total proteins were extracted. The expression levels of p38, phospho-p38 and CREB were analyzed by Western blotting; (b,d) Cells were treated with 0.2 μΜ/mL curcumol for 0, 3, 6, 12, 24, and 48 h. The whole cell lysates were prepared to test the expression levels of p38 and phospho-p38. Equal protein loading was evaluated by β-actin; and (e) Cells were treated with SB203580 and curcumol for 48 h after AnnexinV-FITC/PI staining flow cytometry analysis was performed. Representative data are shown from three independent experiments.
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ijms-16-19851-f005: Involvement of p38 MAPK pathway in the anti-tumor effect of curcumol. (a,c) Cells were treated with curcumol (0, 0.05, 0.1, 0.2 and 0.4 μΜ/mL) for 48 h, and the total proteins were extracted. The expression levels of p38, phospho-p38 and CREB were analyzed by Western blotting; (b,d) Cells were treated with 0.2 μΜ/mL curcumol for 0, 3, 6, 12, 24, and 48 h. The whole cell lysates were prepared to test the expression levels of p38 and phospho-p38. Equal protein loading was evaluated by β-actin; and (e) Cells were treated with SB203580 and curcumol for 48 h after AnnexinV-FITC/PI staining flow cytometry analysis was performed. Representative data are shown from three independent experiments.

Mentions: MAPK intracellular signaling cascades are involved in the IGF-1R mediated signals pathways [17,24]. It is reported that p38 MAPK acts as a tumor suppressor in various cancer cells [21,26,27], Liu showed that activation of ERK1/2 and suppression of p38 MAPK pathways might be the molecular mechanisms for the malignant behavior of colon cancer cells [28]. Hui has indicated that activation of p38 MAPK could induce apoptosis in colorectal carcinoma cells [29]. To clearly understand the underlying molecular signaling pathways by which curcumol exerted anti-proliferation effect on colorectal cancer cells, we investigated the effects of curcumol on MAPK pathways by Western blot analysis. As shown in Figure 5a,c, we found that increasing concentrations of curcumol significantly increased the expression of phosphorylated p38 and decreased the CREB expression in a dose-dependent manner, while it had no effect on the total levels of p38. Furthermore, we detected the levels of p38 and phosphorylated p38 at the different points. The increase of phosphorylated p38 was observed over time in curcumol-treated LoVo cells (Figure 5b,d). In addition, LoVo cells were treated with p38 inhibitor SB203580. No obvious cell number changes were found in SB203580-treated groups from 0.5 to 5 μM concentration (according the protocol of SB203580). Then, we performed an apoptotic assay by flow cytometry in LoVo cells upon treatment with SB203580, curcumol, or SB203580 combined with curcumol, and the results show that the presence of apoptotic LoVo cells following curcumol treatment (Figure 5e). Combined with the FCM results, our study demonstrated that curcumol induced LoVo cells apoptosis via activation of p38 MAPK and its downstream signal pathway.


Curcumol Inhibits Growth and Induces Apoptosis of Colorectal Cancer LoVo Cell Line via IGF-1R and p38 MAPK Pathway.

Wang J, Huang F, Bai Z, Chi B, Wu J, Chen X - Int J Mol Sci (2015)

Involvement of p38 MAPK pathway in the anti-tumor effect of curcumol. (a,c) Cells were treated with curcumol (0, 0.05, 0.1, 0.2 and 0.4 μΜ/mL) for 48 h, and the total proteins were extracted. The expression levels of p38, phospho-p38 and CREB were analyzed by Western blotting; (b,d) Cells were treated with 0.2 μΜ/mL curcumol for 0, 3, 6, 12, 24, and 48 h. The whole cell lysates were prepared to test the expression levels of p38 and phospho-p38. Equal protein loading was evaluated by β-actin; and (e) Cells were treated with SB203580 and curcumol for 48 h after AnnexinV-FITC/PI staining flow cytometry analysis was performed. Representative data are shown from three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581329&req=5

ijms-16-19851-f005: Involvement of p38 MAPK pathway in the anti-tumor effect of curcumol. (a,c) Cells were treated with curcumol (0, 0.05, 0.1, 0.2 and 0.4 μΜ/mL) for 48 h, and the total proteins were extracted. The expression levels of p38, phospho-p38 and CREB were analyzed by Western blotting; (b,d) Cells were treated with 0.2 μΜ/mL curcumol for 0, 3, 6, 12, 24, and 48 h. The whole cell lysates were prepared to test the expression levels of p38 and phospho-p38. Equal protein loading was evaluated by β-actin; and (e) Cells were treated with SB203580 and curcumol for 48 h after AnnexinV-FITC/PI staining flow cytometry analysis was performed. Representative data are shown from three independent experiments.
Mentions: MAPK intracellular signaling cascades are involved in the IGF-1R mediated signals pathways [17,24]. It is reported that p38 MAPK acts as a tumor suppressor in various cancer cells [21,26,27], Liu showed that activation of ERK1/2 and suppression of p38 MAPK pathways might be the molecular mechanisms for the malignant behavior of colon cancer cells [28]. Hui has indicated that activation of p38 MAPK could induce apoptosis in colorectal carcinoma cells [29]. To clearly understand the underlying molecular signaling pathways by which curcumol exerted anti-proliferation effect on colorectal cancer cells, we investigated the effects of curcumol on MAPK pathways by Western blot analysis. As shown in Figure 5a,c, we found that increasing concentrations of curcumol significantly increased the expression of phosphorylated p38 and decreased the CREB expression in a dose-dependent manner, while it had no effect on the total levels of p38. Furthermore, we detected the levels of p38 and phosphorylated p38 at the different points. The increase of phosphorylated p38 was observed over time in curcumol-treated LoVo cells (Figure 5b,d). In addition, LoVo cells were treated with p38 inhibitor SB203580. No obvious cell number changes were found in SB203580-treated groups from 0.5 to 5 μM concentration (according the protocol of SB203580). Then, we performed an apoptotic assay by flow cytometry in LoVo cells upon treatment with SB203580, curcumol, or SB203580 combined with curcumol, and the results show that the presence of apoptotic LoVo cells following curcumol treatment (Figure 5e). Combined with the FCM results, our study demonstrated that curcumol induced LoVo cells apoptosis via activation of p38 MAPK and its downstream signal pathway.

Bottom Line: Though many researchers have reported curcumol and its bioactivity, the potential molecular mechanism for its anti-cancer effect in colorectal cancer LoVo cells still remains unclear.In the present study, we found that curcumol showed growth inhibition and induced apoptosis of LoVo cells in a dose- and time-dependent manner.The occurrence of its proliferation inhibition and apoptosis came with suppression of IGF-1R expression, and then increased the phosphorylation of p38 mitogen activated protein kinase (MAPK), which might result in a cascade response by inhibiting the CREB survival pathway and finally triggered Bax/Bcl-2 and poly(ADP-ribose) polymerase 1 (PARP-1) apoptosis signals.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Guilin Medical University, Guilin 541004, China. wujiacaiwjc@hotmail.com.

ABSTRACT
Curcumol, isolated from the traditional medical plant Rhizoma Curcumae, is the bioactive component of Zedoary oil, whose potential anti-tumor effect has attracted considerable attention in recent years. Though many researchers have reported curcumol and its bioactivity, the potential molecular mechanism for its anti-cancer effect in colorectal cancer LoVo cells still remains unclear. In the present study, we found that curcumol showed growth inhibition and induced apoptosis of LoVo cells in a dose- and time-dependent manner. The occurrence of its proliferation inhibition and apoptosis came with suppression of IGF-1R expression, and then increased the phosphorylation of p38 mitogen activated protein kinase (MAPK), which might result in a cascade response by inhibiting the CREB survival pathway and finally triggered Bax/Bcl-2 and poly(ADP-ribose) polymerase 1 (PARP-1) apoptosis signals. Moreover, curcumol inhibited colorectal cancer in xenograft models of nude mice. Immunohistochemical and Western blot analysis revealed that curcumol could decrease the expression of ki-67, Bcl-2 as well as CREB1, and increase the expression of Bax and the phosphorylation of p38, which were consistent with our in vitro study. Overall, our in vitro and in vivo data confirmed the anti-cancer activity of curcumol, which was related to a significant inhibition of IGF-1R and activation of p38 MAPKs, indicating that curcumol may be a potential anti-tumor agent for colorectal carcinoma therapy.

No MeSH data available.


Related in: MedlinePlus