Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is latent but constitutively activated in many types of cancers. It is well known that STAT3 plays a key role in inflammation-associated tumorigenesis. Curcumin is an anti-inflammatory natural compound isolated from the turmeric (Curcuma longa L., Zingiberaceae) that has been extensively used in a traditional medicine over the centuries. In the present study, we have found that curcumin inhibits STAT3 signaling that is persistently overactivated in H-Ras transformed breast epithelial cells (H-Ras MCF10A). Specific cysteine residues present in STAT3 appear to be critical for the activity as well as conformation of this transcription factor. We identified the cysteine residue 259 of STAT3 as a putative site for curcumin binding. Site-directed mutation of this cysteine residue abolished curcumin-induced inactivation of STAT3 and apoptosis in H-Ras MCF10A cells. The α,β-unsaturated carbonyl moiety of curcumin appears to be essential in its binding to STAT3 in H-Ras MCF10A cells. Tetrahydrocurcumin that lacks such electrophilic moiety failed to interact with STAT3 and to induce apoptosis in the same cell line. Taken together, our findings suggest that curcumin can abrogate aberrant activation of STAT3 through direct interaction, thereby inhibiting STAT3-mediated mammary carcinogenesis.

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These results suggest that MEIB may serve as a potential drug candidate for the treatment of human OSCC.

5-fluorouracil (5-FU) is a chemotherapeutic agent commonly used for treatment of solid tumors, including colorectal cancer. However, chemoresistance against 5-fluorouracil (5-FU) often limits its success for chemotherapy and, therefore, finding out appropriate adjuvant(s) that might overcome chemoresistance against 5-FU bears a significant importance. In the present study, we have found that α-mangostin can sensitize 5-FU-resistant SNUC5/5-FUR colon cancer cells to apoptosis. Exposure of α-mangostin induced significant DNA damages and increased the intracellular 8-hydroxyguanosine (8-OH-G) and 4-hydroxynonenal (4-HNE) levels in SNUC5 and SNUC5/5-FUR cells. Western blot analysis illustrated that α-mangostin-induced apoptosis was mediated by the activation of the extrinsic and intrinsic pathways in SNUC5/5-FUR cells. In particular, we observed that Fas receptor (FasR) level was lower in SNUC5/5-FUR cells, compared with SNUC5 cells and that silencing FasR attenuated α-mangostin-mediated apoptosis in SNUC5/5-FUR cells. Together, our study illustrates that α-mangostin might be an efficient apoptosis sensitizer that can overcome chemoresistance against 5-FU by activating apoptosis pathway.

AMPK (AMP‐activated protein kinase) as an anti‐cancer target has been received attention since it functions as an upstream regulator of proliferative proteins such as tuberous sclerosis complex (TSC), mammalian target of rapamycin (mTOR), p70S6 kinase, and elongation factor‐2. Upon activation, mTOR, a cell survival molecule, exhibits uncontrolled proliferation and dysregulation of apoptosis. CSK (C‐terminal Src kinase) is an inactivator of Src and Src‐family protein kinases, proto‐oncogenes that play a role in cell survival and cell proliferation. In this study, we examined the regulation of AMPK/mTOR pathway in HT‐29 colon cancer cells and AMPK/CSK signaling in HepG2 hepato‐carcinoma cells treated with EGCG. EGCG decreased cell viability, and increased apoptotic cell death in both types of cells. The stimulation of AMPK by EGCG resulted in the down‐regulation of mTOR in HT‐29 cells and up‐regulation of CSK activities through decreasing inactive form in HepG2 cells. The application of AMPK siRNA supported the evidence that AMPK acts as an upstream signal of mTOR in cells treated with EGCG. In HepG2 cells, AMPK was found to act as a positive regulator of CSK. [This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (NO. R01‐2008‐000‐20131‐0)]