The JNK Signaling Pathway Is a Novel Molecular Target for S-Propargyl- L-Cysteine, a Naturally-Occurring Garlic Derivatives: Link to Its Anticancer Activity in Pancreatic Cancer In Vitro and In Vivo
Pancreatic ductal adenocarcinoma (PDA) remains a devastating disease worldwide.
Although significant improvement has been made in understanding its pathophysiology, only small
portion of patients with PDA are likely to benefit from curative surgery and current chemotherapy.
Thus, there is an urgent need for developing novel effective therapeutic approaches to the treatment of
PDA. Today, garlic products have become an important source of effective compounds for the treatment of cancer. We
have recently identified a novel garlic active component, S-propargyl-L-cysteine (SPRC), an analogue of S-Allyl Cysteine
(SAC). Although its anticancer activity has been shown against several cancers, the mechanism of action is not fully
understood. The present study was first designed to determine the anticancer activity of SPRC in PDA and the underlying
mechanisms of action in vitro and in vivo. Our results demonstrated that SPRC reduced cell viability and colony
formation, inhibited cell proliferation, induced G2/M phase cell cycle arrest and apoptosis in human PDA cells with
various p53 statuses (HPAC, p53 wt; Panc-1, p53 mt). Furthermore, SPRC inhibited tumor growth in Panc-1 xenograft
models. We also demonstrated that SPRC achieved its anticancer effects by regulation of the JNK protein levels through
increasing its phosphorylation and decreasing its polyubiquitination-mediated degradation. In conclusion, SPRC has
significant anti-PDA activity and the effects do not depend on p53 status, presumably through activating the JNK
signaling pathway, providing a basis for the development of this compound as a novel target anticancer therapeutic agent
Keywords: Apoptosis, chemotherapy, garlic derivative, JNK, pancreatic cancer, SPRC.
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