Sunitinib induces apoptosis in pheochromocytoma tumor cells by inhibiting VEGFR2/Akt/mTOR/S6K1 pathways through modulation of Bcl-2 and BAD

2012 ◽  
Vol 302 (6) ◽  
pp. E615-E625 ◽  
Author(s):  
Yuria Saito ◽  
Yuko Tanaka ◽  
Yuichi Aita ◽  
Kiyo-aki Ishii ◽  
Tatsuhiko Ikeda ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Pc12 Cells ◽  
Kinase Inhibitor ◽  
Active Agent ◽  
Dependent Manner ◽  
Human Neuroblastoma ◽  
Downstream Effectors ◽  
Apoptotic Effect ◽  
Induced Apoptosis ◽  
Apoptotic Effects

Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity that mainly targets vascular endothelial growth factor receptors (VEGFRs). Very recently, sunitinib has been shown to be an active agent for the treatment of malignant pheochromocytomas. However, it is unclear whether sunitinib acts only through an antiangiogenic mechanism or whether it may also directly target tumor cells. Sunitinib markedly induced apoptosis of PC12 cells in a dose-dependent and time-dependent manner. Furthermore, in support of these findings, we found that sunitinib induced a reduction in the expression of the antiapoptotic molecule Bcl-2 as well as dephosphorylation of the proapoptotic molecule BAD, which results in the activation of BAD in these cells. Consistent with these apoptotic effects, our results showed that sunitinib inhibited phosphorylation of Akt and mTOR and was followed by a reduction of S6K1, which is a well-known target of mTOR. Knockdown of VEGFR-2 attenuated the sunitinib-induced effects, including apoptosis and inhibition of signaling pathways such as the phosphorylation of Akt as well as mTOR, and Bcl-2, which confirmed that these effects could be mediated by VEGFR-2. In addition, silencing of S6K1 induced apoptosis accompanied by a decrease in the phosphorylation of BAD and Bcl-2, similar to that observed with sunitinib treatment. Thus, these results together suggest that sunitinib initially exerts its apoptotic effect through the inhibition of VEGFR-2, which, when followed by reduction of its downstream effectors, including Akt/mTOR/S6K1, may lead to inhibition of the antiapoptotic molecule Bcl-2 and activation of the proapoptotic molecule BAD in PC12 cells. However, PC12 cells do not precisely reflect the pathogenesis of malignant cells. Therefore, we confirmed the key findings by replicating these experiments in human neuroblastoma SK-N-SH cells.

Unscheduled re-entry into the cell cycle induced by NGF precedes cell death in nascent retinal neurones

2000 ◽  
Vol 113 (7) ◽  
pp. 1139-1148 ◽  
Author(s):  
J.M. Frade
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Ganglion Cells ◽  
Neurotrophin Receptor ◽  
Dependent Manner ◽  
Apoptotic Effect ◽  
Induced Apoptosis

During their early postmitotic life, a proportion of the nascent retinal ganglion cells (RGCs) are induced to die as a result of the interaction of nerve growth factor (NGF) with the neurotrophin receptor p75. To analyse the mechanisms by which NGF promotes apoptosis, an in vitro culture system consisting of dissociated E5 retinal cells was established. In this system, NGF-induced apoptosis was only observed in the presence of insulin and neurotrophin-3, conditions that favour the birth of RGCs and other neurones expressing the glycoprotein G4. The pro-apoptotic effect of NGF on the G4-positive neurones was evident after 10 hours in vitro and was preceded by a significant upregulation of cyclin B2, but not cyclin D1, and the presence of mitotic nuclei in these cells. Brain-derived neurotrophic factor prevented both the increase of cyclin B2 expression in the G4-positive neurones and the NGF-induced cell death. Finally, pharmacologically blocking cell-cycle progression using the cyclin-dependent kinase inhibitor roscovitine prevented NGF-induced cell death in a dose-dependent manner. These results strongly suggest that the apoptotic signalling initiated by NGF requires a driving stimulus manifested by the neuronal birth and is preceded by the unscheduled re-entry of postmitotic neurones into the cell cycle.

scholarly journals Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Tien-Jyun Chang ◽  
Hsing-Chi Tseng ◽  
Meng-Wei Liu ◽  
Yi-Cheng Chang ◽  
Meng-Lun Hsieh ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Mitochondrial Function ◽  
Cell Apoptosis ◽  
Beta Cell Apoptosis ◽  
Ampk Activation ◽  
Apoptotic Effect ◽  
Glucagon Like Peptide 1 ◽  
Induced Apoptosis ◽  
Apoptotic Effects

Abstract Accumulation of methylglyoxal (MG) contributes to glucotoxicity and mediates beta cell apoptosis. The molecular mechanism by which GLP-1 protects MG-induced beta cell apoptosis remains unclear. Metformin is a first-line drug for treating type 2 diabetes associated with AMPK activation. However, whether metformin prevents MG-induced beta cell apoptosis is controversial. Here, we explored the signaling pathway involved in the anti-apoptotic effect of GLP-1, and investigated whether metformin had an anti-apoptotic effect on beta cells. MG treatment induced apoptosis of beta cells, impaired mitochondrial function, and prolonged activation of AMP-dependent protein kinase (AMPK). The MG-induced pro-apoptotic effects were abolished by an AMPK inhibitor. Pretreatment of GLP-1 reversed MG-induced apoptosis, and mitochondrial dysfunction, and suppressed prolonged AMPK activation. Pretreatment of GLP-1 reversed AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR)-induced apoptosis, and suppressed prolonged AMPK activation. However, metformin neither leads to beta cell apoptosis nor ameliorates MG-induced beta cell apoptosis. In parallel, GLP-1 also prevents MG-induced beta cell apoptosis through PKA and PI3K-dependent pathway. In conclusion, these data indicates GLP-1 but not metformin protects MG-induced beta cell apoptosis through improving mitochondrial function, and alleviating the prolonged AMPK activation. Whether adding GLP-1 to metformin provides better beta cell survival and delays disease progression remains to be validated.

scholarly journals Extracellular Matrix Proteins Modulate Antimigratory and Apoptotic Effects of Doxorubicin

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Georges Said ◽  
Marie Guilbert ◽  
Hamid Morjani ◽  
Roselyne Garnotel ◽  
Pierre Jeannesson ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tumor Cells ◽  
Topoisomerase I ◽  
Type I Collagen ◽  
De Novo ◽  
Acquired Resistance ◽  
Chemotherapeutic Agents ◽  
Type I ◽  
Induced Apoptosis ◽  
Apoptotic Effects

Anticancer drug resistance is a multifactorial process that includes acquired and de novo drug resistances. Acquired resistance develops during treatment, while de novo resistance is the primary way for tumor cells to escape chemotherapy. Tumor microenvironment has been recently shown to be one of the important factors contributing to de novo resistance and called environment-mediated drug resistance (EMDR). Two forms of EMDR have been described: soluble factor-mediated drug resistance (SFM-DR) and cell adhesion-mediated drug resistance (CAM-DR). Anthracyclines, among the most potent chemotherapeutic agents, are widely used in clinics against hematopoietic and solid tumors. Their main mechanism of action relies on the inhibition of topoisomerase I and/or II and the induction of apoptosis. Beyond this well-known antitumor activity, it has been recently demonstrated that anthracyclines may display potent anti-invasive effects when used at subtoxic concentrations. In this paper, we will describe two particular modes of EMDR by which microenvironment may influence tumor-cell response to one of these anthracyclines, doxorubicin. The first one considers the influence of type I collagen on the antimigratory effect of doxorubicin (CAM-DR). The second considers the protection of tumor cells by thrombospondin-I against doxorubicin-induced apoptosis (SFM-DR).

N-Acetylphytosphingosine Enhances the Radiosensitivity of Tumor Cells by Increasing Apoptosis

2005 ◽  
Vol 277-279 ◽  
pp. 536-541
Author(s):  
Young Soo Han ◽  
Yun Hwa Kim ◽  
Yeon Sook Yun ◽  
Soo Jin Jeon ◽  
Ki Sung Kim ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Mammalian Cells ◽  
Second Messengers ◽  
Clonogenic Survival ◽  
Jurkat Cells ◽  
Human Leukemia ◽  
Apoptotic Effect ◽  
Radiation Induced ◽  
Induced Apoptosis ◽  
Exogenous Treatment

Ceramides are well-known second messengers which mediate apoptosis, proliferation, differentiation in mammalian cells, but the physiological roles of phytosphingosines are poorly understood. We hypothesized that one of the phytosphingosine derivatives, N-acetylphytosphingosine (NAPS) can induce apoptosis in human leukemia Jurkat cell line and increase apoptosis in irradiated MDA-MB-231 cells. We first examined the effect of NAPS on apoptosis of Jurkat cells. NAPS had a more rapid and stronger apoptotic effect than C2-ceramide in Jurkat cells and significant increase of apoptosis was observed at 3 h after treatment. In contrast, the apoptosis induced by C2-ceramide was observed only after 16 h of treatment. NAPS induced apoptosis was mediated by caspase 3 and 8 activation and inhibited by z-VAD-fmk. Ceramide plays a pivotal role in radiation induced apoptosis. We postulated that exogenous treatment of NAPS sensitizes tumor cells to ionizing radiation, since NAPS might be used as a more effective alternative to C2-ceramide. As expected, NAPS decreased clonogenic survival of irradiated MDA-MB-231 cells dose dependently, and apoptosis of irradiated cells in the presence of NAPS was increased through the caspase activation. Taken together, NAPS is an effective apoptosis-inducing agent, which can be readily synthesized from yeast sources, and is a potent alternative to ceramide for the further study of ceramide associated signaling and the development of radiosensitizing agent.

GAS-6 Rescues Endothelial Cells from Apoptosis through FOXO1 Inactivation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3686-3686
Author(s):  
Jorge Ganopolsky ◽  
Brian Varnum ◽  
Mark Blostein
Keyword(s):  
Endothelial Cells ◽  
Kinase Inhibitor ◽  
Pi3 Kinase ◽  
Serum Starvation ◽  
Specific Gene ◽  
Dependent Manner ◽  
Akt Phosphorylation ◽  
Mediate Cell ◽  
Induced Apoptosis ◽  
First Time

Abstract Growth Arrest Specific gene product 6 (GAS-6), a γ-carboxylated protein expressed in quiescent fibroblasts and endothelial cells, exerts an anti-apoptotic function by binding to the receptor tyrosine kinase Axl. Recently, our laboratory has demonstrated that gas6-Axl interactions activate PI3-kinase with subsequent Akt phosphorylation during gas6-mediated protection from apoptosis. The current study explores further the mechanism by which this survival mechanism is achieved. FOXO1 is a member of the Forkhead family of transcription factors that plays a role in the expression of pro-apoptototic genes. Phosphorylation of FOXO1 at Thr24, Ser256 and Ser319 results in phospho-FOXO1 translocation from the nucleus to the cytoplasm, with consequent suppression of FOXO1 transcriptional activity and inhibition of apoptosis. In the present study we show, for the first time, that the treatment of serum-starved endothelial cells with 100 ng/ml of GAS-6 induces FOXO1 phosphorylation in a time dependent manner. Phosphorylated FOXO1 is translocated from the nucleus to the cytoplasm as evidenced by Western blot analysis of both nuclear and cytoplasmic extracts. Using fluorescence microscopy, FOXO1 is found predominantly in the nucleus during apoptosis induced by serum starvation. Upon gas6 stimulation, phosphorylated FOXO1 is translocated to the cytoplasm (see Figure 1). It is suggested that anti-apoptotic genes are then released from suppression and are thereby able to mediate cell survival. Both FOXO1 phosphorylation and translocation are suppressed by Wortmannin, a PI3-kinase inhibitor demonstrating that FOXO1 phosphorylation is PI3-kinase dependent. These results provide mechanistic insight of how gas6 rescues endothelial cells from serum-starvation-induced apoptosis. Foxo1 distribution Foxo1 distribution

Induction of RKIP and Inhibition of the Transcription Repressor YY1 in B-NHL by the Novel Proteasome Inhibitor NPI-0052 and Sensitization to TRAIL-Induced Apoptosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2391-2391
Author(s):  
Eriko Suzuki ◽  
Sara Huerta-Yepez ◽  
Stavroula Baritaki ◽  
Michael Palladino ◽  
Benjamin Bonavida
Keyword(s):  
Monoclonal Antibodies ◽  
Tumor Cells ◽  
Proteasome Inhibitor ◽  
Kinase Inhibitor ◽  
Proteasome Inhibitors ◽  
Annexin V ◽  
Underlying Mechanism ◽  
Significant Inhibition ◽  
The Novel ◽  
Induced Apoptosis

Abstract Proteasome inhibitors have been shown to exert multiple effects including direct cytotoxic activity in sensitive cancer cells. In addition, proteasome inhibitors have recently been used therapeutically for certain cancers such as multiple myeloma and mantle cell lymphoma. We have recently reported that the novel proteasome inhibitor, NPI-0052 (Nereus Pharmaceuticals), can sensitize drug-resistant B-NHL tumor cells to apoptosis by various chemotherapeutic drugs. Also, NPI-0052 inhibits the NF-κB survival pathway and inhibition of NF-κB sensitizes tumor cells to TRAIL-induced apoptosis. We hypothesized that inhibition of NF-κB by NPI-0052 may also lead to sensitization of TRAIL-resistant B-NHL cells to TRAIL-mediated apoptosis. Human Burkitt’s lymphoma,Ramos cells, were treated with various concentrations of NPI-0052 (0–10ng/ml for 24h) and were then treated with recombinant human TRAIL (0–100ng/ml for 24h). The cells were examined for apoptosis by Annexin V/PI. The combination treatment resulted in significant potentiation of cytotoxicity and synergy in apoptosis was achieved. We have then examined a potential underlying mechanism of NPI-0052-mediated sensitization. The transcription repressor YY1 was recently shown to negatively regulate the transcription of the TRAIL death receptor DR5 and thus overexpression of YY1 is a resistant factor for TRAIL-induced apoptosis. Hence, treatment of Ramos cells with NPI-0052 resulted in significant inhibition of YY1 expression and upregulation of surface DR5 expression. We have also examined the effect of NPI-0052 on RKIP (Raf-kinase inhibitor protein) (Yeung et al., Molecular Cellular Biology; 21:7207, 2001) expression. Since both NPI-0052 and RKIP inhibit the NF-κB pathway, we hypothesized that treatment of Ramos cells with NPI-0052 may result in significant upregulation of RKIP expression. The findings, indeed, demonstrate that NPI-0052 significantly induced RKIP expression in Ramos cells. Overall, the findings show, for the first time, that NPI-0052 sensitizes B-NHL tumor cells to TRAIL-mediated apoptosis. Sensitization by NPI-0052 was correlated with both the induction of RKIP expression and inhibition of YY1 and upregulation of DR5 expression. Currently, TRAIL or agonist monoclonal antibodies against DR4 or DR5 are being examined clinically for anti-tumor activity. Therefore, our findings suggest the potential application of the combination of NPI-0052 and TRAIL or agonistic monoclonal antibodies against DR4 or DR5 in the treatment of tumor cells that are resistant to drugs and TRAIL.

Molecular Mechanism by Which Rituximab Sensitizes B-NHL Cells to TRAIL Apoptosis: Induction of RKIP and DR5 Expression Via Inhibition of NF-Kb, Snail, and YY1.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1596-1596
Author(s):  
Mario I. Vega ◽  
Melisa Martinez-Paniagua ◽  
Sara Huerta-Yepez ◽  
Yeung Kam ◽  
Stavroula Baritaki ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Proteasome Inhibitors ◽  
Underlying Mechanism ◽  
Inhibitor Protein ◽  
Rt Pcr ◽  
Yin Yang 1 ◽  
Induced Apoptosis

Abstract There have been significant advances in the treatment of patients with B-NHL using combination of rituximab and CHOP. However, a subset of patients does not initially respond or develop resistance to further treatments; hence, the need for alternative therapies to overcome resistance. TRAIL and agonist DR4/DR5 monoclonal antibodies have been examined clinically against a variety of tumors in Phase I/II. However, the majority of B-NHL derived from patients and cell lines are resistant to TRAIL-induced apoptosis. Recent findings demonstrated that treatment of TRAIL-resistant-B-NHL with rituximab sensitizes the tumor cells to TRAIL apoptosis. The underlying mechanism of rituximab-induced sensitization to TRAIL, however, is not clear. We have recently reported that treatment of tumor cells with sensitizing agents (example CDDP, proteasome inhibitors) resulted in the reversal of resistance to TRAIL via induction of Raf-1 kinase inhibitor protein (RKIP) and demonstrated the pivotal role of RKIP in the regulation of tumor cell sensitivity to TRAIL. Hence, since rituximab induces the expression of RKIP in B-NHL, we determined the role of RKIP induction by rituximab in the sensitization of B-NHL to TRAIL apoptosis. Various B-NHL cell lines were used as models for study. Treatment of B-NHL cells with rituximab (20 ng/ml) and TRAIL (5–10 ng/ml) resulted in significant potentiation of apoptosis and synergy was achieved. Rituximab induced the expression of RKIP as determined by RT-PCR and western concomitantly with inhibition of NF-kB. The inhibition of NF-kB resulted in upregulation of RKIP expression and was mediated, in large part, by inhibition of the transcription repressor Snail (downstream of NF-kB). Further, RKIP-induced inhibition of NF-kB by rituximab resulted in downstream inhibition of the DR5 transcription repressor Yin Yang 1 (YY1) and concomitantly with the upregulation of DR5 expression. The role of RKIP induction by rituximab in the upregulation of DR5 and sensitization to TRAIL apoptosis was corroborated by the use of cells over expressing RKIP which were sensitive to TRAIL apoptosis in the absence of rituximab. Our findings reveal a novel mechanism of rituximab-induced sensitization of B-NHL to TRAIL apoptosis via inhibition of NF-kB and Snail and upregulation of RKIP and DR-5. The combination of rituximab and TRAIL may be effective in the treatment of B-NHL. Further, our studies suggest that agents other than rituximab that can induce RKIP can reverse resistance to TRAIL in B-NHL that are unresponsive to rituximab treatment.

scholarly journals Adenosine Deaminase Inhibitor EHNA Exhibits a Potent Anticancer Effect Against Malignant Pleural Mesothelioma

2015 ◽  
Vol 35 (1) ◽  
pp. 51-60 ◽  
Author(s):  
Yasuhiro Nakajima ◽  
Takeshi Kanno ◽  
Toshio Nagaya ◽  
Kozo Kuribayashi ◽  
Takashi Nakano ◽  
...  
Keyword(s):  
Adenosine Deaminase ◽  
Cell Lines ◽  
Malignant Pleural Mesothelioma ◽  
Kinase Inhibitor ◽  
Treatment Time ◽  
Adenosine Kinase ◽  
Tunel Staining ◽  
Pleural Mesothelioma ◽  
Dependent Manner ◽  
Induced Apoptosis

Background/Aims: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor and an effective therapy has been little provided as yet. The present study investigated the possibility for the adenosine deaminase (ADA) inhibitor EHNA as a target of MPM treatment. Methods: MTT assay, TUNEL staining, monitoring of intracellular adenosine concentrations, and Western blotting were carried out in cultured human MPM cell lines without and with knocking-down ADA. The in vivo effect of EHNA was assessed in mice inoculated with NCI-H2052 MPM cells. Results: EHNA induced apoptosis of human MPM cell lines in a concentration (0.01-1 mM)- and treatment time (24-48 h)-dependent manner, but such effect was not obtained with another ADA inhibitor pentostatin. EHNA increased intracellular adenosine concentrations in a treatment time (3-9 h)-dependent manner. EHNA-induced apoptosis of MPM cells was mimicked by knocking-down ADA, and the effect was neutralized by the adenosine kinase inhibitor ABT-702. EHNA clearly suppressed tumor growth in mice inoculated with NCI-H2052 MPM cells. Conclusion: The results of the present study show that EHNA induces apoptosis of MPM cells by increasing intracellular adenosine concentrations, to convert to AMP, and effectively prevents MPM cell proliferation. This suggests that EHNA may be useful for treatment of the tragic neoplasm MPM.

scholarly journals Alantolactone inhibits cell autophagy and promotes apoptosis through targeting AP2M1 in acute lymphotic leukemia

2020 ◽  
Author(s):  
Ce Shi ◽  
Zhenkun Wang ◽  
Dongguang Yang ◽  
Jia Wei ◽  
Zhiyu Liu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Dependent Manner ◽  
Nude Mouse Model ◽  
Hematopoietic Malignancy ◽  
Apoptotic Effect ◽  
Induced Apoptosis

Abstract Background: Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most common in children. Alantolactone (ALT) has been reported to have antitumor activity in different types of cancers. This study aimed to investigate the antitumor activity and molecular mechanism of ALT in ALL. Methods: The ALL cell lines were treated with 1, 5 and 10μM of ALT, and then subjected to MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assays were employed to measure cell apoptosis and autophagy. Meanwhile, Western blot analysis was used to detect apoptosis and autophagy related proteins. Finally, the effect of ALT on tumor growth was measured in BV173 xenograft nude mouse model. Results: In this study, we demonstrated that ALT inhibited the proliferation of ALL cells in does-dependent manner. A series of experiments demonstrated that ALT inhibited cell proliferation, colony formation, autophagy, induced apoptosis and restained tumor growth in vivo through upregulating adaptor related protein complex 2 subunit mu 1 (AP2M1). Moreover, autophagy activator rapamycin attenuated the pro-apoptotic effect of ALT on BV173 and NALM6 cell lines. Further, overexpressed AP2M1 decreased the expression of Beclin1, LC3-II/LC3-1 ratio and increased p62 expression. Fianally, knockdown of Beclin1 increased the levels of bax, cleaved caspase 3 and cytochrome C and decreased bcl-2 expression. Conclusions: This study demonstrated that ALT exerts antitumor activity through inducing apoptosis and inhibiting autophagy by upregulating AP2M1 in ALL, indicating a potential therapeutic strategy for ALL treatment.

Cudraxanthone H Induces Growth Inhibition and Apoptosis in Oral Cancer Cells via NF-κB and PIN1 Pathways

2015 ◽  
Vol 43 (07) ◽  
pp. 1439-1452 ◽  
Author(s):  
Hwa-Jeong Lee ◽  
Seong-Suk Jue ◽  
Soo-Kyung Kang ◽  
Won-Jung Bae ◽  
Youn-Chul Kim ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Kinase Inhibitor ◽  
Human Cancer ◽  
Annexin V ◽  
Root Bark ◽  
Dependent Manner ◽  
Human Cancer Cells ◽  
Induced Apoptosis

Cudraxanthone H (CH) is a natural compound isolated from a methanol extract of the root bark of Cudrania tricuspidata, a herbal plant also known as Moraceae. However, the effect of CH on human cancer cells has not been reported previously. The aim of this study was to investigate the anticancer effects and mechanism of action of CH on oral squamous cell carcinoma (OSCC) cells. CH exerted significant antiproliferative effects on OSCC cells in dose- and time-dependent manners. CH also induced apoptosis in OSCC cells, as evidenced by an increased percentage of cells in the sub-G1 phase of the cell cycle, annexin V-positive/propidium iodide-negative cells, and nuclear morphology. This antiproliferative effect of CH was associated with a marked reduction in the expression of cyclin D1 and cyclin E, with a concomitant induction of cyclin-dependent kinase inhibitor (CDKI) expression (p21 and p27). CH inhibited the phosphorylation and degradation of I[Formula: see text]B-[Formula: see text]and the nuclear translocation of NF-[Formula: see text]B p65. Furthermore, CH treatment down-regulated PIN1 mRNA and protein expression in a dose-dependent manner. PIN1 overexpression by infection with adenovirus-PIN1 (Ad-PIN1) attenuated the CH-induced growth-inhibiting and apoptosis-inducing effects, blocked CH-enhanced CDKI expression and restored cyclin levels. In contrast, inhibiting PIN1 expression via juglone exerted the opposite effects. The present study is the first to demonstrate antiproliferative and apoptosis-inducing effects of CH, which exerts its effects by inhibiting NF-[Formula: see text]B and PIN1. These data suggest that it might be a novel alternative chemotherapeutic agent for use in the treatment of oral cancer.

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