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ApoG2 induces cell cycle arrest of nasopharyngeal carcinoma cells by suppressing the c-Myc signaling pathway.

Hu ZY, Sun J, Zhu XF, Yang D, Zeng YX - J Transl Med (2009)

Bottom Line: The results of cell cycle analysis showed that the downregulation of c-Myc signaling pathway by siRNA interference could cause a significant arrest of NPC cell at S phase of the cell cycle.In CNE-2 xenografts, ApoG2 significantly downregulated the expression of c-Myc and suppressed tumor growth in vivo.This data suggested that the inhibitory effect of ApoG2 on NPC cell cycle proliferation might contribute to its use in anticancer therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: State Key Laboratory of Oncology in South China and Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, PR China. huzheyu24@gmail.com

ABSTRACT

Background: apogossypolone (ApoG2) is a novel derivate of gossypol. We previously have reported that ApoG2 is a promising compound that kills nasopharyngeal carcinoma (NPC) cells by inhibiting the antiapoptotic function of Bcl-2 proteins. However, some researchers demonstrate that the antiproliferative effect of gossypol on breast cancer cells is mediated by induction of cell cycle arrest. So this study was aimed to investigate the effect of ApoG2 on cell cycle proliferation in NPC cells.

Results: We found that ApoG2 significantly suppressed the expression of c-Myc in NPC cells and induced arrest at the DNA synthesis (S) phase in a large percentage of NPC cells. Immunoblot analysis showed that expression of c-Myc protein was significantly downregulated by ApoG2 and that the expression of c-Myc's downstream molecules cyclin D1 and cyclin E were inhibited whereas p21 was induced. To further identify the cause-effect relationship between the suppression of c-Myc signaling pathway and induction of cell cycle arrest, the expression of c-Myc was interfered by siRNA. The results of cell cycle analysis showed that the downregulation of c-Myc signaling pathway by siRNA interference could cause a significant arrest of NPC cell at S phase of the cell cycle. In CNE-2 xenografts, ApoG2 significantly downregulated the expression of c-Myc and suppressed tumor growth in vivo.

Conclusion: Our findings indicated that ApoG2 could potently disturb the proliferation of NPC cells by suppressing c-Myc signaling pathway. This data suggested that the inhibitory effect of ApoG2 on NPC cell cycle proliferation might contribute to its use in anticancer therapy.

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Treatment with ApoG2 induces alterations in the expression of c-Myc, p21, and cyclins. (A) The effect of ApoG2 on the expression of c-Myc. CNE-2 cells were incubated with 10 μM ApoG2 for 24 to 72 h, and cell lysates were analyzed using immunoblotting. (B) The effect of ApoG2 on the expression of molecules downstream from c-Myc. After treatment with ApoG2, CNE-2 cell lysates were analyzed using immunoblotting with anti-p21, -cyclin D1, -cyclin E, and -p53 antibodies. (C) The effect of ApoG2 on cell cycle-regulatory molecules in HONE-1 cells. Cells were treated with 10 μM ApoG2 for 24 to 72 h, and cell lysates were analyzed using immunoblotting.
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Figure 3: Treatment with ApoG2 induces alterations in the expression of c-Myc, p21, and cyclins. (A) The effect of ApoG2 on the expression of c-Myc. CNE-2 cells were incubated with 10 μM ApoG2 for 24 to 72 h, and cell lysates were analyzed using immunoblotting. (B) The effect of ApoG2 on the expression of molecules downstream from c-Myc. After treatment with ApoG2, CNE-2 cell lysates were analyzed using immunoblotting with anti-p21, -cyclin D1, -cyclin E, and -p53 antibodies. (C) The effect of ApoG2 on cell cycle-regulatory molecules in HONE-1 cells. Cells were treated with 10 μM ApoG2 for 24 to 72 h, and cell lysates were analyzed using immunoblotting.

Mentions: Because researchers have reported that cell cycle-regulating molecules, such as p21, p53, and TGF-β1, play roles in gossypol-induced cell cycle arrest [9,14], we hypothesized that ApoG2 can also modify some cell cycle regulators, resulting in cell cycle arrest in NPC cells. Consistent with our hypothesis, treatment with 10 μM ApoG2 significantly decreased the level of c-Myc protein expression at 24 h in CNE-2 cells (Fig. 3A). Moreover, expression of p21 protein was upregulated as early as 24 h and gradually returned to low level at 72 h since most of the CNE-2 cells were dead at this time (Fig. 3B); unlike p21, expression of both cyclin D1 and cyclin E were downregulated following the degradation of c-Myc. We observed no changes in p53 protein expression (Fig. 3B). Similar changes in the c-Myc pathway were also detected in ApoG2-treated HONE-1 cells (Fig. 3C), which was in agreement with the results of cell cycle analysis that ApoG2 induced cell cycle arrest in both sensitive CNE-2 cells and insensitive HONE-1 cells.


ApoG2 induces cell cycle arrest of nasopharyngeal carcinoma cells by suppressing the c-Myc signaling pathway.

Hu ZY, Sun J, Zhu XF, Yang D, Zeng YX - J Transl Med (2009)

Treatment with ApoG2 induces alterations in the expression of c-Myc, p21, and cyclins. (A) The effect of ApoG2 on the expression of c-Myc. CNE-2 cells were incubated with 10 μM ApoG2 for 24 to 72 h, and cell lysates were analyzed using immunoblotting. (B) The effect of ApoG2 on the expression of molecules downstream from c-Myc. After treatment with ApoG2, CNE-2 cell lysates were analyzed using immunoblotting with anti-p21, -cyclin D1, -cyclin E, and -p53 antibodies. (C) The effect of ApoG2 on cell cycle-regulatory molecules in HONE-1 cells. Cells were treated with 10 μM ApoG2 for 24 to 72 h, and cell lysates were analyzed using immunoblotting.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2742515&req=5

Figure 3: Treatment with ApoG2 induces alterations in the expression of c-Myc, p21, and cyclins. (A) The effect of ApoG2 on the expression of c-Myc. CNE-2 cells were incubated with 10 μM ApoG2 for 24 to 72 h, and cell lysates were analyzed using immunoblotting. (B) The effect of ApoG2 on the expression of molecules downstream from c-Myc. After treatment with ApoG2, CNE-2 cell lysates were analyzed using immunoblotting with anti-p21, -cyclin D1, -cyclin E, and -p53 antibodies. (C) The effect of ApoG2 on cell cycle-regulatory molecules in HONE-1 cells. Cells were treated with 10 μM ApoG2 for 24 to 72 h, and cell lysates were analyzed using immunoblotting.
Mentions: Because researchers have reported that cell cycle-regulating molecules, such as p21, p53, and TGF-β1, play roles in gossypol-induced cell cycle arrest [9,14], we hypothesized that ApoG2 can also modify some cell cycle regulators, resulting in cell cycle arrest in NPC cells. Consistent with our hypothesis, treatment with 10 μM ApoG2 significantly decreased the level of c-Myc protein expression at 24 h in CNE-2 cells (Fig. 3A). Moreover, expression of p21 protein was upregulated as early as 24 h and gradually returned to low level at 72 h since most of the CNE-2 cells were dead at this time (Fig. 3B); unlike p21, expression of both cyclin D1 and cyclin E were downregulated following the degradation of c-Myc. We observed no changes in p53 protein expression (Fig. 3B). Similar changes in the c-Myc pathway were also detected in ApoG2-treated HONE-1 cells (Fig. 3C), which was in agreement with the results of cell cycle analysis that ApoG2 induced cell cycle arrest in both sensitive CNE-2 cells and insensitive HONE-1 cells.

Bottom Line: The results of cell cycle analysis showed that the downregulation of c-Myc signaling pathway by siRNA interference could cause a significant arrest of NPC cell at S phase of the cell cycle.In CNE-2 xenografts, ApoG2 significantly downregulated the expression of c-Myc and suppressed tumor growth in vivo.This data suggested that the inhibitory effect of ApoG2 on NPC cell cycle proliferation might contribute to its use in anticancer therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: State Key Laboratory of Oncology in South China and Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, PR China. huzheyu24@gmail.com

ABSTRACT

Background: apogossypolone (ApoG2) is a novel derivate of gossypol. We previously have reported that ApoG2 is a promising compound that kills nasopharyngeal carcinoma (NPC) cells by inhibiting the antiapoptotic function of Bcl-2 proteins. However, some researchers demonstrate that the antiproliferative effect of gossypol on breast cancer cells is mediated by induction of cell cycle arrest. So this study was aimed to investigate the effect of ApoG2 on cell cycle proliferation in NPC cells.

Results: We found that ApoG2 significantly suppressed the expression of c-Myc in NPC cells and induced arrest at the DNA synthesis (S) phase in a large percentage of NPC cells. Immunoblot analysis showed that expression of c-Myc protein was significantly downregulated by ApoG2 and that the expression of c-Myc's downstream molecules cyclin D1 and cyclin E were inhibited whereas p21 was induced. To further identify the cause-effect relationship between the suppression of c-Myc signaling pathway and induction of cell cycle arrest, the expression of c-Myc was interfered by siRNA. The results of cell cycle analysis showed that the downregulation of c-Myc signaling pathway by siRNA interference could cause a significant arrest of NPC cell at S phase of the cell cycle. In CNE-2 xenografts, ApoG2 significantly downregulated the expression of c-Myc and suppressed tumor growth in vivo.

Conclusion: Our findings indicated that ApoG2 could potently disturb the proliferation of NPC cells by suppressing c-Myc signaling pathway. This data suggested that the inhibitory effect of ApoG2 on NPC cell cycle proliferation might contribute to its use in anticancer therapy.

Show MeSH
Related in: MedlinePlus