Sulforaphane inhibits hypoxia-induced HIF-1α and VEGF expression and migration of human colon cancer cells

Abstract

Abstract. The effects of sulforaphane (a natural product commonly found in broccoli) was investigated on hypoxia inducible factor-1α (HIF-1α) expression in HCT116 human colon cancer cells and AGS human gastric cancer cells. We found that hypoxia-induced HIF-1α protein expression in HCT116 and AGS cells, while treatment with sulforaphane markedly and concentration-dependently inhibited HIF-1α expression in both cell lines. Treatment with sulforaphane inhibited hypoxia-induced vascular endothelial growth factor (VEGF) expression in HCT116 cells. Treatment with sulforaphane modulated the effect of hypoxia on HIF-1α stability. However, degradation of HIF-1α by sulforaphane was not mediated through the 26S proteasome pathway. We also found that the inhibition of HIF-1α by sulforaphane was not mediated through AKT and extracellular signal-regulated kinase phosphorylation under hypoxic conditions. Finally, hypoxiainduced HCT116 cell migration was inhibited by sulforaphane. These data suggest that sulforaphane may inhibit human colon cancer progression and cancer cell angiogenesis by inhibiting HIF-1α and VEGF expression. Taken together, these results indicate that sulforaphane is a new and potent chemopreventive drug candidate for treating patients with human colon cancer. IntroductionHypoxic conditions are associated with increased tumor growth and metastasis, as well as poor survival in cancer patients (1). Hypoxia inducible factor-1α (HIF-1α) is a key protein that is expressed under hypoxic conditions and promotes vascular remodeling by vascular endothelial growth factor (VEGF). VEGF is one of the most critical factors that stimulate angiogenesis. Therefore, inhibition of HIF -1α and VEGF has demonstrated therapeutic efficacy in the treatment of several types of cancer. Expression of VEGF is regulated by hypoxia, growth factors, and oncogenes (2). HIF-1 is a heterodimeric transcription factor composed of HIF-1α and aryl hydrocarbon receptor nuclear translocator (ARNT, HIF-1β), which translocates to the nucleus and binds to hypoxia response element (HRE) binding sites. Under normoxic conditions, HIF-1α protein is efficiently degraded by the ubiquitin protein ligase Von Hippel-Lindeau (VHL) and thus does not exert its effects (3). Several compounds have been tested as inhibitors of hypoxia-induced HIF-1α expression in cancer cells (4-6).Various natural products and their analogues are currently being researched as chemopreventive agents (7-9). Sulforaphane is a potent isothiocyanate derivative found in broccoli and other vegetables, such as Brussels sprouts and cabbage, and has various health benefits, including anticancer and antioxidant properties (8,10). Many studies have revealed that sulforaphane activates phase 2 antioxidant enzymes via nuclear factor E2-related factor 2 (Nrf2) (11)(12)(13)(14). In the last decade, many studies revealed that sulforaphane acts as a chemopreventive agent by inducing apoptosis and cell cycle arrest and inhibiting proliferation. In colon cancer cells, sulforaphane induced apoptosis ...

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

“…Among all ITCs, PEITC and sulforaphane (SFN) have been highlighted not only due to their antiproliferative effects, but also for their ability to induce apoptosis and to impair CRC metastatic spread by reducing cell migration, invasion and cell growth in anchorage-independent conditions [18,19,20,21,22,23,24,25]. Moreover, both ITCs have also proved to exert anticancer effects and target CSCs of several solid tumors [26,27,28,29,30].…”

Sulforaphane suppresses EMT and metastasis in human lung cancer through miR-616-5p-mediated GSK3β/β-catenin signaling pathways

“…Many studies have examined the anti-cancer effects of sulforaphane in control of tumorigenesis or progression of lung cancer [1] , breast cancer [2] , prostate cancer [3] and digestive system neoplasms [4][5][6] . However, the effect of sulforaphane on lung cancer metastasis, which limits the lifespan of lung cancer patients, has not been explored.…”

Stress Response of Dietary Phytochemicals in a Hormetic Manner for Health and Longevity

“…In a mouse study, sulfate inhibited proteasomal and autophagic activation and cytotoxicity resulting from proteasomal impairment [113]. Sulforaphane inhibited HIF-1α expression in HCT116 human colon cancer cells and AGS human gastric cancer cells, but inhibited hypoxiainduced VEGF expression only in HCT116 cells [114]. Sulforaphane affects the stress-response pathways and can show protective effects, especially against neurodegeneration and cancer.…”