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.
Highlights
The transcription factor hypoxia-inducible factor-1 (HIF-1) plays a pivotal role in regulating the initiation of genes that are involved in decisive aspects of cancer biology, such as angiogenesis, cell survival, differentiation, invasion, tumor progression, and glucose metabolism [1,2,3,4,5,6]
Two main signaling pathways are involved in the regulation of Hypoxia inducible factor-1α (HIF-1α) function and protein levels: the phosphatidylinositol 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK) pathways [4]
To investigate whether Salternamide A (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
Summary
The transcription factor hypoxia-inducible factor-1 (HIF-1) plays a pivotal role in regulating the initiation of genes that are involved in decisive aspects of cancer biology, such as angiogenesis, cell survival, differentiation, invasion, tumor progression, and glucose metabolism [1,2,3,4,5,6]. HIF-1 activity in tumors depends on the availability of the HIF-1α subunit and the levels of HIF-1α expression under hypoxic conditions [4]. The overexpression of HIF-1α is due to the fundamental interaction between various metabolic pathways and factors that lead to particular genetic alterations and extracellular stimuli, such as hypoxia that impact both protein degradation and synthesis [10]. Two main signaling pathways are involved in the regulation of HIF-1α function and protein levels: the phosphatidylinositol 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK) pathways [4].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
