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Colorectal cancer displays elevated cyclooxygenase-2 (COX-2) expression, and several studies have suggested that COX-2 expression is associated with parameters of aggressive colon cancer. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, and recent studies indicate that AMPK activation strongly suppresses cell proliferation in nonmalignant cells as well as in tumor cells. As a metabolic sensing signal, AMPK is involved in cancer cell apoptosis. In HT-29 colon cancer cells, the regulation of COX-2 expression by treating with TPA (12- O-tetradecanoylphorbol-13-acetate), low-level H2O2, high-level H2O2, and finally the combinations of TPA and low H2O2 or high H2O2 was investigated. We found that COX-2 expression levels with treatment reacted as follows: with TPA alone > TPA and low H2O2 > low H2O2 > high H2O2 > TPA and high H2O2. COX-2 regulation by these agents was accompanied by the alteration of AMPK control. The apoptotic bodies were detected as follows: high level of H2O2 > TPA > low level of H2O2. The present findings suggest that both COX-2 stimulators (TPA and H2O2) might have differential effects on COX-2 and AMPK regulation and further apoptotic regulation. [ABSTRACT FROM AUTHOR]

This study investigated the apoptotic regulation by green tea catechin epigallcatechin-3-gallate (EGCG) on colon cancer cells in the presence of low-dose H2O2 known to exert the activation of signal pathways leading to cell proliferation. In the presence of low-dose H2O2, EGCG induced apoptosis and abolished the cell-proliferative effect exhibited by low-dose H2O2. This reduction of growth was accompanied by an activation of AMP-activated kinase (AMPK), a decrease in cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) levels, and the induction of apoptotic markers such as p53 and poly(ADP-ribose) polymerase (PARP) cleavage. The low-dose H2O2 stimulated COX-2 expression, and treating cells with synthetic AMPK activator AICAR (5-aminoimiazole-4-carboxamide-1-β-d-ribofuranoside) resulted in greater suppression of COX-2 expression and PGE2. By treating cells with high concentrations of the reactive oxygen species (ROS) scavenger NAC ( N-acetyl-1-cysteine), the apoptotic effect of EGCG was abolished and led to suppression of AMPK and COX-2, indicating that the liberation of excessive ROS might be the upstream signal of the AMPK–COX-2 signaling pathway even in the presence of low-dose H2O2. [ABSTRACT FROM AUTHOR]

This study investigated the apoptotic regulation by green tea catechin epigallcatechin-3-gallate (EGCG) on colon cancer cells in the presence of low-dose H2O2 known to exert the activation of signal pathways leading to cell proliferation. In the presence of low-dose H2O2, EGCG induced apoptosis and abolished the cell-proliferative effect exhibited by low-dose H2O2. This reduction of growth was accompanied by an activation of AMP-activated kinase (AMPK), a decrease in cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) levels, and the induction of apoptotic markers such as p53 and poly(ADP-ribose) polymerase (PARP) cleavage. The low-dose H2O2 stimulated COX-2 expression, and treating cells with synthetic AMPK activator AICAR (5-aminoimiazole-4-carboxamide-1-β-d-ribofuranoside) resulted in greater suppression of COX-2 expression and PGE2. By treating cells with high concentrations of the reactive oxygen species (ROS) scavenger NAC ( N-acetyl-1-cysteine), the apoptotic effect of EGCG was abolished and led to suppression of AMPK and COX-2, indicating that the liberation of excessive ROS might be the upstream signal of the AMPK–COX-2 signaling pathway even in the presence of low-dose H2O2. [ABSTRACT FROM AUTHOR]

Selenium has received much attention as an anticancer agent, although the mechanisms of action underlying its pro-apoptotic properties remain unclear. Tumors that respond well to antioxidant treatments, such as hepatocellular carcinoma (HCC), may benefit from treatment with selenium as this compound also has antioxidant properties. Furthermore, a major oncogenic driver in HCC is the nuclear transcription co-activator, β-catenin. In the present study, we examined the mechanism by which selenium reduces survival of HCC cells, and whether this was associated with modulation of the β-catenin pathway. Hep3B cell lines and cancer cell xenografted animals were treated with selenium, and apoptotic events or signals such as AMPK, β-catenin and GSK3β were determined. Further interactions among β-catenin, glycogen synthase kinase 3β (GSK3β), and AMPK were explored by applying AMPK small interfering RNA (siRNA) or GSK3β siRNA with western blotting or immunofluorescence microscopic observation. Selenium activated AMPK, which in turn suppressed β-catenin. Selenium induced the translocation of AMPK into the nucleus and prevented the accumulation of β-catenin therein. Upon inactivation of AMPK by AMPK siRNA, selenium no longer modulated β-catenin, implying that AMPK is an upstream signal for β-catenin. We found that the binding between AMPK and β-catenin occurs in the cytosolic fraction, and therefore concluded that the cancer cell antiproliferative effects of selenium are mediated by a GSK3β-independent AMPK/β-catenin pathway, although AMPK-mediated GSK3β regulation was also observed. We primarily discovered that AMPK is a crucial regulator initiating selenium-induced inhibition of β-catenin expression. Taken together, these novel findings help to illuminate the molecular mechanisms underlying the anticancer effect of selenium and highlight the regulation of β-catenin by selenium.

In lieu of elucidating bidirectional connecting mechanism between AMP-activated protein kinase (AMPK) and survival signal Akt we applied MCF-7 breast cancer cells to determine whether AMPK modulation alters Akt signals and vice versa. Suppression of Akt activities with a synthetic Akt inhibitor alleviated AMPK activities suggesting that Akt is capable of inhibiting AMPK. Also the activation of AMPK with quercetin strongly abrogated Akt activities. Treating cancer cells with AMPK siRNA or Compound C resulted in marked increment of Akt dephosphorylation indicating that AMPK has antagonistic activities towards Akt. However, quercetin exerted Akt inhibitory activities in the absence of AMPK activation. Quercetin induced partial co-localization of phospho-Akt and phospho-AMPK in the nucleus even though their interaction seems to be indirect since the immunoprecipitation data indicate there was no direct binding between total Akt and AMPK. These results suggest there is a mutual suppressive interaction between AMPK and Akt. The investigation of mutual suppression between Akt and AMPK by chemo-preventive agents such as quercetin may provide a mechanistic rational for controlling breast tumor cell growth.

AMP-activated protein kinase (AMPK) has emerged as a therapeutic target of cancer. AMPK functions as an upstream regulator of proliferative signals such as mammalian target of rapamycin (mTOR), tuberous sclerosis complex (TSC), p70S6 and elongation factor-2, indicating that AMPK can be applied for the inhibition of cancer cell proliferation via modulating the proliferative signaling network. The Akt/mTOR signaling pathway is activated in colon cancer. The well known mTOR inhibitor rapamycin has a disadvantage of feedback stimulation of Akt. Anthocyanins are naturally-occurring mTOR inhibitor possessing Akt inhibitory activities. We have investigated the mTOR inhibitory effect of anthocyanins through the activation of AMPK. In this study, anthocyanins were applied to colon cancer cells and tumor-bearing xenograft models to investigate their anti-proliferative and pro-apoptotic effects, and elucidate the mechanisms that link AMP-activated protein kinase (AMPK) α1 activation to the survival signal of mTOR. Our results indicated that anthocyanins significantly decreased phospho-mTOR comparable to rapamycin, a synthetic mTOR inhibitor, and this inhibitory effect of anthocyanins on mTOR was completely abrogated by inactivating AMPKα1. Furthermore, suppression of cell growth with anthocyanins was also alleviated in the absence of noticeable AMPKα1 activities. For the first time we have found anthocyanins as novel AMPKα1 activators, and in conditions of AMPKα1 inactivation, anthocyanins lost their ability to inhibit mTOR in HT-29 colon cancer cells. The activation of AMPKα1, and the deactivation of mTOR and Akt were observed in anthocyanins-treated tumor-bearing xenograft models. The results from this study suggest that there is a complex interaction between AMPKα1 and mTOR signaling, and anthocyanins are powerful AMPKα1 activators that inhibit cancer cell growth by inhibiting mTOR phosphorylation.

Background: The stem bark of Kalopanax pictus (KP) has been used in traditional medicine to treat rheumatoidal arthritis, neurotic pain and diabetes mellitus in China and Korea. In this study, the mechanism responsible for anti-inflammatory effects of KP was investigated., Methods: We examined the effects of KP on NO production, nitric oxide synthase (iNOS) and HO-1 expression, NF-κB, Nrf2 and MAPK activation in mouse peritoneal macrophages., Results: The aqueous extract of KP inhibited LPS-induced NO secretion as well as inducible iNOS expression, without affecting cell viability. KP suppressed LPS-induced NF-κB activation, phosphorylation and degradation of IκB-α, phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). Furthermore, KP induced HO-1 expression and Nrf2 nuclear translocation., Conclusion: These results suggest that KP has the inhibitory effects on LPS-induced NO production in macrophages through NF-κB suppression and HO-1 induction.

A series of 2,6- and 2,7-bis(styryl)anthracene derivatives with the donors at the styryl group and acceptors at the 9,10-positions have been synthesized, and their two-photon cross sections (Phidelta(max)) were determined. These compounds exhibit a peak two-photon absorptivity (delta(max)) in the range of 700-2500 GM at 780-1030 nm. Values of lambda(max) and Stokes shifts increase as the acceptor is changed to a stronger one. There is also a parallel increase in lambda(2)max and delta(max) with the same variation of the chromophore structure. Both lambda (2)(max)and Phidelta(max) have been optimized by introducing donor-substituted styryl groups at the 2,6-positions and p-cyanophenyl groups at the 9,10-positions, respectively. The effect of a pi center on the two-photon absorption properties has been assessed by comparing the existing data for a variety of D-pi-D derivatives.