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Salternamide A Suppresses Hypoxia-Induced Accumulation of HIF-1α and Induces Apoptosis in Human Colorectal Cancer Cells.

Bach DH, Kim SH, Hong JY, Park HJ, Oh DC, Lee SK - Mar Drugs (2015)

Bottom Line: In addition, SA suppresses the upstream signaling of HIF-1α, such as PI3K/Akt/mTOR, p42/p44 MAPK, and STAT3 signaling under hypoxic conditions.Furthermore, we found that SA induces cell death by stimulating G2/M cell cycle arrest and apoptosis in human colorectal cancer cells.Taken together, SA was identified as a novel small molecule HIF-1α inhibitor from marine natural products and is potentially a leading candidate in the development of anticancer agents.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. bdhiep90@snu.ac.kr.

ABSTRACT
Hypoxia inducible factor-1α (HIF-1α) is an essential regulator of the cellular response to low oxygen concentrations, activating a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1α is overexpressed in various cancers and therefore represents a considerable chemotherapeutic target. Salternamide A (SA), a novel small molecule that is isolated from a halophilic Streptomyces sp., is a potent cytotoxic agent against a variety of human cancer cell lines. However, the mechanisms by which SA inhibits tumor growth remain to be elucidated. In the present study, we demonstrate that SA efficiently inhibits the hypoxia-induced accumulation of HIF-1α in a time- and concentration-dependent manner in various human cancer cells. In addition, SA suppresses the upstream signaling of HIF-1α, such as PI3K/Akt/mTOR, p42/p44 MAPK, and STAT3 signaling under hypoxic conditions. Furthermore, we found that SA induces cell death by stimulating G2/M cell cycle arrest and apoptosis in human colorectal cancer cells. Taken together, SA was identified as a novel small molecule HIF-1α inhibitor from marine natural products and is potentially a leading candidate in the development of anticancer agents.

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Effect of SA on cell cycle distribution in HCT116 human colorectal cancer cells. (A) Anti-proliferative effect of SA on HCT116 cells. HCT116 cells were treated with various concentrations of SA for 72 h, and cell proliferation was determined with the SRB assay. The data represent the mean percentage ± SD compared to the DMSO-treated control group. Each experiment was performed in triplicate (n = 3). * p < 0.05 compared with the control group. (B) HCT116 cells were treated with SA for 24 or 48 h. The cell cycle distribution was analyzed by flow cytometry. (C) Effects of SA on the expression of cell cycle-related proteins in HCT116 colorectal cancer cells. HCT116 cells (2 × 105 cells/mL) were treated with SA for 24 h. Subsequently, the protein expression levels of cell cycle-related proteins were analyzed by Western blotting.
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marinedrugs-13-06962-f004: Effect of SA on cell cycle distribution in HCT116 human colorectal cancer cells. (A) Anti-proliferative effect of SA on HCT116 cells. HCT116 cells were treated with various concentrations of SA for 72 h, and cell proliferation was determined with the SRB assay. The data represent the mean percentage ± SD compared to the DMSO-treated control group. Each experiment was performed in triplicate (n = 3). * p < 0.05 compared with the control group. (B) HCT116 cells were treated with SA for 24 or 48 h. The cell cycle distribution was analyzed by flow cytometry. (C) Effects of SA on the expression of cell cycle-related proteins in HCT116 colorectal cancer cells. HCT116 cells (2 × 105 cells/mL) were treated with SA for 24 h. Subsequently, the protein expression levels of cell cycle-related proteins were analyzed by Western blotting.

Mentions: A previous study revealed the anti-proliferative activity of SA in a panel of cancer cell lines [16]. To further elucidate the mechanism of action of the anti-proliferative activity of SA, the effect of SA on the regulation of the cell cycle was determined in HCT116 cells. When treated with SA for 72 h, SA primarily inhibited the growth of HCT116 cells in a concentration-dependent manner (Figure 4A). SA (10 μM) increased the cell population in the sub-G1 phase at 48 h (Figure 4B, right panel). To further elucidate whether cell cycle arrest is associated with the regulation of cell cycle checkpoint proteins, the expression of G2/M cell cycle regulatory proteins was analyzed by Western blotting. As shown in Figure 4C, the expression of p-CDC25C (Ser216), CDC25C, p-CDC2 (Thr161), CDC2, cyclin B1, and cyclin A were significantly suppressed, but the levels of p-chk1 (Ser345) and p-chk2 (Thr168) were upregulated by the treatment of SA. These findings suggest that the anti-proliferative activity of SA is associated, in part, with the induction of the G2/M phase cell cycle arrest by modulating cell cycle regulators in HCT116 cells.


Salternamide A Suppresses Hypoxia-Induced Accumulation of HIF-1α and Induces Apoptosis in Human Colorectal Cancer Cells.

Bach DH, Kim SH, Hong JY, Park HJ, Oh DC, Lee SK - Mar Drugs (2015)

Effect of SA on cell cycle distribution in HCT116 human colorectal cancer cells. (A) Anti-proliferative effect of SA on HCT116 cells. HCT116 cells were treated with various concentrations of SA for 72 h, and cell proliferation was determined with the SRB assay. The data represent the mean percentage ± SD compared to the DMSO-treated control group. Each experiment was performed in triplicate (n = 3). * p < 0.05 compared with the control group. (B) HCT116 cells were treated with SA for 24 or 48 h. The cell cycle distribution was analyzed by flow cytometry. (C) Effects of SA on the expression of cell cycle-related proteins in HCT116 colorectal cancer cells. HCT116 cells (2 × 105 cells/mL) were treated with SA for 24 h. Subsequently, the protein expression levels of cell cycle-related proteins were analyzed by Western blotting.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663561&req=5

marinedrugs-13-06962-f004: Effect of SA on cell cycle distribution in HCT116 human colorectal cancer cells. (A) Anti-proliferative effect of SA on HCT116 cells. HCT116 cells were treated with various concentrations of SA for 72 h, and cell proliferation was determined with the SRB assay. The data represent the mean percentage ± SD compared to the DMSO-treated control group. Each experiment was performed in triplicate (n = 3). * p < 0.05 compared with the control group. (B) HCT116 cells were treated with SA for 24 or 48 h. The cell cycle distribution was analyzed by flow cytometry. (C) Effects of SA on the expression of cell cycle-related proteins in HCT116 colorectal cancer cells. HCT116 cells (2 × 105 cells/mL) were treated with SA for 24 h. Subsequently, the protein expression levels of cell cycle-related proteins were analyzed by Western blotting.
Mentions: A previous study revealed the anti-proliferative activity of SA in a panel of cancer cell lines [16]. To further elucidate the mechanism of action of the anti-proliferative activity of SA, the effect of SA on the regulation of the cell cycle was determined in HCT116 cells. When treated with SA for 72 h, SA primarily inhibited the growth of HCT116 cells in a concentration-dependent manner (Figure 4A). SA (10 μM) increased the cell population in the sub-G1 phase at 48 h (Figure 4B, right panel). To further elucidate whether cell cycle arrest is associated with the regulation of cell cycle checkpoint proteins, the expression of G2/M cell cycle regulatory proteins was analyzed by Western blotting. As shown in Figure 4C, the expression of p-CDC25C (Ser216), CDC25C, p-CDC2 (Thr161), CDC2, cyclin B1, and cyclin A were significantly suppressed, but the levels of p-chk1 (Ser345) and p-chk2 (Thr168) were upregulated by the treatment of SA. These findings suggest that the anti-proliferative activity of SA is associated, in part, with the induction of the G2/M phase cell cycle arrest by modulating cell cycle regulators in HCT116 cells.

Bottom Line: In addition, SA suppresses the upstream signaling of HIF-1α, such as PI3K/Akt/mTOR, p42/p44 MAPK, and STAT3 signaling under hypoxic conditions.Furthermore, we found that SA induces cell death by stimulating G2/M cell cycle arrest and apoptosis in human colorectal cancer cells.Taken together, SA was identified as a novel small molecule HIF-1α inhibitor from marine natural products and is potentially a leading candidate in the development of anticancer agents.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. bdhiep90@snu.ac.kr.

ABSTRACT
Hypoxia inducible factor-1α (HIF-1α) is an essential regulator of the cellular response to low oxygen concentrations, activating a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1α is overexpressed in various cancers and therefore represents a considerable chemotherapeutic target. Salternamide A (SA), a novel small molecule that is isolated from a halophilic Streptomyces sp., is a potent cytotoxic agent against a variety of human cancer cell lines. However, the mechanisms by which SA inhibits tumor growth remain to be elucidated. In the present study, we demonstrate that SA efficiently inhibits the hypoxia-induced accumulation of HIF-1α in a time- and concentration-dependent manner in various human cancer cells. In addition, SA suppresses the upstream signaling of HIF-1α, such as PI3K/Akt/mTOR, p42/p44 MAPK, and STAT3 signaling under hypoxic conditions. Furthermore, we found that SA induces cell death by stimulating G2/M cell cycle arrest and apoptosis in human colorectal cancer cells. Taken together, SA was identified as a novel small molecule HIF-1α inhibitor from marine natural products and is potentially a leading candidate in the development of anticancer agents.

Show MeSH
Related in: MedlinePlus