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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 the degradation of HIF-1α. (A) HCT116 cells were treated with a proteasome inhibitor (10 μM MG132) and 10 μM SA under normoxic or hypoxic conditions before immunoblotting; (B) for VHL and Hsp90 immunoblotting, HCT116 cells were treated with SA and cultured for 8 h under normoxic or hypoxic conditions, respectively.
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marinedrugs-13-06962-f002: Effect of SA on the degradation of HIF-1α. (A) HCT116 cells were treated with a proteasome inhibitor (10 μM MG132) and 10 μM SA under normoxic or hypoxic conditions before immunoblotting; (B) for VHL and Hsp90 immunoblotting, HCT116 cells were treated with SA and cultured for 8 h under normoxic or hypoxic conditions, respectively.

Mentions: In general, the accumulation of HIF-1α depends on the balance between its degradation and synthesis (translation) [18]. To determine whether SA is able to suppress HIF-1α protein accumulation by promoting its degradation, the cells were pretreated with the proteasome inhibitor MG132, followed by SA treatment in HCT116 cells. As shown in Figure 2A, pretreatment with MG132 resulted in the accumulation of HIF-1α, but SA efficiently abrogated the accumulation of HIF-1α despite proteasome suppression, indicating that SA decreases HIF-1α protein accumulation through a pathway independent of proteasomal degradation.


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 the degradation of HIF-1α. (A) HCT116 cells were treated with a proteasome inhibitor (10 μM MG132) and 10 μM SA under normoxic or hypoxic conditions before immunoblotting; (B) for VHL and Hsp90 immunoblotting, HCT116 cells were treated with SA and cultured for 8 h under normoxic or hypoxic conditions, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

marinedrugs-13-06962-f002: Effect of SA on the degradation of HIF-1α. (A) HCT116 cells were treated with a proteasome inhibitor (10 μM MG132) and 10 μM SA under normoxic or hypoxic conditions before immunoblotting; (B) for VHL and Hsp90 immunoblotting, HCT116 cells were treated with SA and cultured for 8 h under normoxic or hypoxic conditions, respectively.
Mentions: In general, the accumulation of HIF-1α depends on the balance between its degradation and synthesis (translation) [18]. To determine whether SA is able to suppress HIF-1α protein accumulation by promoting its degradation, the cells were pretreated with the proteasome inhibitor MG132, followed by SA treatment in HCT116 cells. As shown in Figure 2A, pretreatment with MG132 resulted in the accumulation of HIF-1α, but SA efficiently abrogated the accumulation of HIF-1α despite proteasome suppression, indicating that SA decreases HIF-1α protein accumulation through a pathway independent of proteasomal degradation.

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