**1. Introduction**

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 [1–6]. HIF-1 is a heterodimer that consists of HIF-1α and HIF-1β subunits. In addition, 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]. Indeed, HIF-1α is overexpressed in a variety of human cancers compared to normal tissues [7,8]. Consequently, HIF-1α is an appealing intracellular target for treating a wide range of hypoxia-related pathologies by targeted cancer therapy [9].

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]. Signaling from the PI3K pathway enhances HIF-1α synthesis through the mammalian target of the rapamycin protein complex (mTOR; a kinase that functions downstream of PI3K and Akt), likely by heightening HIF-1α translation. The p42/p44 MAPK pathway may induce the transactivation function of HIF-1α through the direct phosphorylation of HIF-1α [11] or by upregulating its cofactor p300 [12]. Additionally, recent studies have reported that the signal transducer and activator of transcription-3 (STAT3) is activated in response to hypoxia, a common feature of various solid tumors [13,14]. Activated STAT3 also mediates the upregulation of HIF-1α by enhancing its transcriptional activity [15].

Salternamide A (SA), a novel small molecule marine agent, was recently isolated by our group from a halophilic *Streptomyces* sp. possessing anti-proliferative activity against various cancer cells [16]. SA was identified as the first secondary metabolite from a saltern-derived actinomycetes microorganism and the first chlorinated member of the manumycin family. However, there has been no report further evaluating its anticancer activity and mechanisms of action in human colon cancer cells.

In the present study, we attempted to investigate the mechanism by which SA suppresses HIF-1α protein accumulation and induces cell death in HCT116 human colon cancer cells.
