Abstract
The Signal Transducer and Activator of Transcription (STAT) proteins comprise a family of latent transcription factors with diverse functions. STAT3 has well established roles in cell proliferation, growth and survival, and its persistent activation has been detected with high frequency in many human cancers. As constitutive activation of STAT3 appears to be vital for the continued survival of these cancerous cells, it has emerged as an attractive target for chemotherapeutics. We examined whether the inhibitory activities of bioactive compounds from cruciferous vegetables, such as Benzyl isothiocyanate (BITC) and sulforaphane, extended to STAT3 activation in PANC-1 human pancreatic cancer cells. BITC and sulforaphane were both capable of inhibiting cell viability and inducing apoptosis in PANC-1. Sulforaphane had minimal effect on the direct inhibition of STAT3 tyrosine phosphorylation, however, suggesting its inhibitory activities are most likely STAT3-independent. Conversely, BITC was shown to inhibit the tyrosine phosphorylation of STAT3, but not the phosphorylation of ERK1/2, MAPK and p70S6 kinase. These results suggest that STAT3 may be one of the targets of BITC-mediated inhibition of cell viability in PANC-1 cancer cells. In addition, we show that BITC can prevent the induction of STAT3 activation by Interleukin-6 in MDA-MB-453 breast cancer cells. Furthermore, combinations of BITC and sulforaphane inhibited cell viability and STAT3 phosphorylation more dramatically than either agent alone. These findings suggest that the combination of the dietary agents BITC and sulforaphane has potent inhibitory activity in pancreatic cancer cells and that they may have translational potential as chemopreventative or therapeutic agents.
Highlights
Despite major advances in the detection and treatment of cancer in the past few decades, cancers of the pancreas are still rarely curable; the five-year survival rate of pancreatic cancer patients remains less than 5% [1]
Sulforaphane and Benzyl isothiocyanate (BITC) inhibit cell viability and induce apoptosis in PANC-1 pancreatic cancer cells We first examined the effect of sulforaphane and BITC treatment on the viability of PANC-1 as determined by MTT assays
We investigated the effect of sulforaphane treatment on the phosphorylation status of STAT3
Summary
Despite major advances in the detection and treatment of cancer in the past few decades, cancers of the pancreas are still rarely curable; the five-year survival rate of pancreatic cancer patients remains less than 5% [1]. The etiology of pancreatic cancer is poorly understood, but it involves the multi-stage development of aberrations in signaling pathways that affect cell growth and proliferation [3]. STAT3 is a member of the STAT family of transcription factors, which is transiently activated in response to cytokine and growth factor receptor stimulation [5,6,7,8]. It plays necessary roles in early development, the presence of STAT3 in the majority of adult tissue and cell types is mostly dispensable [9,10,11]. The inhibition of STAT3 by a variety of means has been demonstrated to exert a potent anti-cancer effect [15,21,22]
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