Allyl Isothiocyanate Inhibits Invasion and Angiogenesis in Breast Cancer via EGFR Mediated JAK1/STAT3 Signaling Pathway

Abstract

Angiogenesis, invasion, and metastasis are the main events of cancer cells. JAK1/STAT3 is a key intracellular signaling transduction path, which controls the growth, differentiation, apoptosis, invasion, and angiogenesis in various cancer cells. The existing study explored the impact of AITC on the JAK-1/STAT-3 pathway in DMBAinjected rat mammary tumorigenesis. The mammary tumor was initiated through a single dose of 25 mg DMBA/rat through a subcutaneous injection administered near the mammary gland. We observed decreased body weight and augmented the total number of tumors, tumor incidence, tumor volume, well-developed tumor, and histopathological abnormalities in DMBA-injected rats and that were modulated after being treated with AITC. Staining of mammary tissues showed a high accumulation of collagen in DMBAtreated rats and it was normalized by the AITC treatment. Moreover, DMBA-induced mammary tissues showed up-regulated expressions of EGFR, pJAK-1, pSTAT-3, the nuclear fraction of STAT-3, and its associated products like VEGF, VEGFR2, HIF-1α, MMP-2, and MMP-9 and the down-regulated expressions of cytosolic STAT-3 and TIMP-2. Oral administration of AITC on DMBAtreated rats inhibits angiogenesis and invasion through modified these angiogenic and invasive markers. The finding of the current study is further confirmed by molecular docking analysis that shows a strong binding interaction between AITC with STAT-3 and cocrystal structure of STAT3 glide energy of -18.123 and − 72.246 (kcal/mole), respectively. Overall, the results suggested that AITC inhibits activation of the JAK-1/STAT-3 path, which subsequently prevents angiogenesis and invasion. It was recommended that AITC might develop a beneficial effect against breast cancer.

(R)-8-Methylsulfinyloctyl isothiocyanate from Nasturtium officinale inhibits LPS-induced immunoinflammatory responses in mouse peritoneal macrophages: chemical synthesis and molecular signaling pathways involved

“…This signalling pathway has also been shown to be affected by other ITCs such as 3-methylsulfinylpropyl ITC (iberin) or AITC in a TR146 cell line and in an animal model of DMBA-induced rat mammary tumorigenesis. 81,82…”

Research progress in tumor angiogenesis and drug resistance in breast cancer

“…EGF is a mediator with crucial roles in the proliferation, survival, differentiation, and migration of vascular endothelial cells, through EGFR binding. EGFR is activated by phosphorylation and is involved in regulation of tumor angiogenesis via its downstream signaling pathways (MAPK, PI3K/AKT/ PKB, STAT, and PLCγ/PKC) 21 (Figure 1). HER2, a subtype of EGFR, is a frequent target in breast cancer treatment.…”

“…HER2, a subtype of EGFR, is a frequent target in breast cancer treatment. EGFRmediated downregulation of the JAK-1/STAT-3 signaling pathway has been found to inhibit angiogenesis, significantly decrease the volume of breast cancer tissues, and inhibit tumor growth 21 . EGFR and VEGFR frequently share downstream signaling pathways.…”