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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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Proposed signaling pathways underlying the effects of SA on the suppression of HIF-1α and the induction of cell death in human colorectal cancer cells.
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marinedrugs-13-06962-f006: Proposed signaling pathways underlying the effects of SA on the suppression of HIF-1α and the induction of cell death in human colorectal cancer cells.

Mentions: Salternamide A was identified for the first time as an inhibitor of HIF-1α accumulation under hypoxic conditions in cancer cells (Figure 6). The translational regulation of HIF-1α accumulation by SA was partly associated with the down-regulation of the axis of the PI3K/mTOR/STAT3 signaling pathways. The anti-proliferative activity of SA in HCT116 colorectal cancer cells was also associated with G2/M cell cycle arrest and apoptotic/autophagic cell deaths. Therefore, SA is a leading candidate for the development of anticancer agents, and these mechanisms will be a key therapeutic target for pharmacologic and therapeutic intervention in HIF-1α-driven tumor growth and cell death.


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)

Proposed signaling pathways underlying the effects of SA on the suppression of HIF-1α and the induction of cell death in human colorectal cancer cells.
© Copyright Policy
Related In: Results  -  Collection

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

marinedrugs-13-06962-f006: Proposed signaling pathways underlying the effects of SA on the suppression of HIF-1α and the induction of cell death in human colorectal cancer cells.
Mentions: Salternamide A was identified for the first time as an inhibitor of HIF-1α accumulation under hypoxic conditions in cancer cells (Figure 6). The translational regulation of HIF-1α accumulation by SA was partly associated with the down-regulation of the axis of the PI3K/mTOR/STAT3 signaling pathways. The anti-proliferative activity of SA in HCT116 colorectal cancer cells was also associated with G2/M cell cycle arrest and apoptotic/autophagic cell deaths. Therefore, SA is a leading candidate for the development of anticancer agents, and these mechanisms will be a key therapeutic target for pharmacologic and therapeutic intervention in HIF-1α-driven tumor growth and cell death.

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