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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-response protein expressions. (A) HCT116 cells were treated at the indicated time points under normoxic or hypoxic conditions in the presence or absence of SA (10 μM) before immunoblotting. (B and C) HCT116 cells were treated for 8 h under normoxic or hypoxic conditions in the presence or absence of increasing SA concentrations.
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marinedrugs-13-06962-f003: Effect of SA on hypoxia-response protein expressions. (A) HCT116 cells were treated at the indicated time points under normoxic or hypoxic conditions in the presence or absence of SA (10 μM) before immunoblotting. (B and C) HCT116 cells were treated for 8 h under normoxic or hypoxic conditions in the presence or absence of increasing SA concentrations.

Mentions: Recent studies have reported that the PI3K/Akt/mTOR and p42/p44 MAPK pathways are associated with the regulation of HIF-1α protein synthesis at the translational level [10,20]. The p42/p44 MAPK also enhances the transcriptional activity of HIF-1α [11]. To address the potential involvement of these pathways in the SA-mediated suppression of HIF-1α accumulation, the expression of the proteins in the signal transduction pathway was determined by Western blot analysis. As shown in Figure 3A, activated (phosphorylated form) PI3K, Akt, mTOR, and RPS6 expression under hypoxic conditions was downregulated by the treatment of SA (10 μM) in a time-dependent manner. A subsequent study also revealed that SA effectively suppressed the expressions of these signaling proteins in a concentration-dependent manner (Figure 3B). In addition, SA also downregulated the activation of p70S6K1 (Thr389), 4E-BP1 (Thr37/46), eIF4E (Ser209), and RPS6 (Ser235/236), which are downstream target molecules of mTOR complex 1 (mTORC1) signaling pathways. Therefore, these data suggest that the suppression of HIF-1α protein expression by SA might be partly associated with the downregulation of mTORC1 signaling pathways under hypoxic conditions.


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-response protein expressions. (A) HCT116 cells were treated at the indicated time points under normoxic or hypoxic conditions in the presence or absence of SA (10 μM) before immunoblotting. (B and C) HCT116 cells were treated for 8 h under normoxic or hypoxic conditions in the presence or absence of increasing SA concentrations.
© Copyright Policy
Related In: Results  -  Collection

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

marinedrugs-13-06962-f003: Effect of SA on hypoxia-response protein expressions. (A) HCT116 cells were treated at the indicated time points under normoxic or hypoxic conditions in the presence or absence of SA (10 μM) before immunoblotting. (B and C) HCT116 cells were treated for 8 h under normoxic or hypoxic conditions in the presence or absence of increasing SA concentrations.
Mentions: Recent studies have reported that the PI3K/Akt/mTOR and p42/p44 MAPK pathways are associated with the regulation of HIF-1α protein synthesis at the translational level [10,20]. The p42/p44 MAPK also enhances the transcriptional activity of HIF-1α [11]. To address the potential involvement of these pathways in the SA-mediated suppression of HIF-1α accumulation, the expression of the proteins in the signal transduction pathway was determined by Western blot analysis. As shown in Figure 3A, activated (phosphorylated form) PI3K, Akt, mTOR, and RPS6 expression under hypoxic conditions was downregulated by the treatment of SA (10 μM) in a time-dependent manner. A subsequent study also revealed that SA effectively suppressed the expressions of these signaling proteins in a concentration-dependent manner (Figure 3B). In addition, SA also downregulated the activation of p70S6K1 (Thr389), 4E-BP1 (Thr37/46), eIF4E (Ser209), and RPS6 (Ser235/236), which are downstream target molecules of mTOR complex 1 (mTORC1) signaling pathways. Therefore, these data suggest that the suppression of HIF-1α protein expression by SA might be partly associated with the downregulation of mTORC1 signaling pathways under hypoxic conditions.

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