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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 hypoxia-induced HIF-1α protein accumulation in various cancer cells. (A) Chemical structure of SA; (B) HCT116 cells were treated at the indicated time points under normoxic or hypoxic conditions (CoCl2 treatment) in the presence or absence of SA (10 μM); (C) HCT116 cells were treated for 8 h under normoxic or hypoxic conditions in the presence or absence of increasing SA concentrations; (D) MDA-MB-231, SK-HEP-1, and SNU-638 cells were treated with 10 μM SA for 8 h under normoxic or hypoxic conditions. Immunoblotting analysis was performed to determine HIF-1α and β-actin protein levels.
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marinedrugs-13-06962-f001: Effect of SA on hypoxia-induced HIF-1α protein accumulation in various cancer cells. (A) Chemical structure of SA; (B) HCT116 cells were treated at the indicated time points under normoxic or hypoxic conditions (CoCl2 treatment) in the presence or absence of SA (10 μM); (C) HCT116 cells were treated for 8 h under normoxic or hypoxic conditions in the presence or absence of increasing SA concentrations; (D) MDA-MB-231, SK-HEP-1, and SNU-638 cells were treated with 10 μM SA for 8 h under normoxic or hypoxic conditions. Immunoblotting analysis was performed to determine HIF-1α and β-actin protein levels.

Mentions: To investigate whether SA (Figure 1A) affects HIF-1α induced by hypoxia, HCT116 cells were exposed to normoxic or hypoxic (CoCl2 treatment) conditions for 2, 4, 8, 12, or 24 h in the presence of 10 μM SA. As shown in Figure 1B, HIF-1α expression was significantly induced by hypoxia-mimetic CoCl2 treatment, starting from as early as 4 h. However, SA effectively suppressed hypoxia-induced HIF-1α protein expression at 8 h along with marked suppression at 12 and 24 h (Figure 1B). In addition, when treated with SA for 8 h under hypoxic conditions, SA suppressed the accumulation of hypoxia-induced HIF-1α protein in a concentration-dependent manner (Figure 1C).


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 hypoxia-induced HIF-1α protein accumulation in various cancer cells. (A) Chemical structure of SA; (B) HCT116 cells were treated at the indicated time points under normoxic or hypoxic conditions (CoCl2 treatment) in the presence or absence of SA (10 μM); (C) HCT116 cells were treated for 8 h under normoxic or hypoxic conditions in the presence or absence of increasing SA concentrations; (D) MDA-MB-231, SK-HEP-1, and SNU-638 cells were treated with 10 μM SA for 8 h under normoxic or hypoxic conditions. Immunoblotting analysis was performed to determine HIF-1α and β-actin protein levels.
© Copyright Policy
Related In: Results  -  Collection

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

marinedrugs-13-06962-f001: Effect of SA on hypoxia-induced HIF-1α protein accumulation in various cancer cells. (A) Chemical structure of SA; (B) HCT116 cells were treated at the indicated time points under normoxic or hypoxic conditions (CoCl2 treatment) in the presence or absence of SA (10 μM); (C) HCT116 cells were treated for 8 h under normoxic or hypoxic conditions in the presence or absence of increasing SA concentrations; (D) MDA-MB-231, SK-HEP-1, and SNU-638 cells were treated with 10 μM SA for 8 h under normoxic or hypoxic conditions. Immunoblotting analysis was performed to determine HIF-1α and β-actin protein levels.
Mentions: To investigate whether SA (Figure 1A) affects HIF-1α induced by hypoxia, HCT116 cells were exposed to normoxic or hypoxic (CoCl2 treatment) conditions for 2, 4, 8, 12, or 24 h in the presence of 10 μM SA. As shown in Figure 1B, HIF-1α expression was significantly induced by hypoxia-mimetic CoCl2 treatment, starting from as early as 4 h. However, SA effectively suppressed hypoxia-induced HIF-1α protein expression at 8 h along with marked suppression at 12 and 24 h (Figure 1B). In addition, when treated with SA for 8 h under hypoxic conditions, SA suppressed the accumulation of hypoxia-induced HIF-1α protein in a concentration-dependent manner (Figure 1C).

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