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2.
Oncotarget ; 9(10): 9206-9218, 2018 Feb 06.
Article in English | MEDLINE | ID: mdl-29507684

ABSTRACT

Metastasis causes high mortality in various malignancies, including prostate cancer (PCa). Accumulating data has suggested that cancer cells spread from the primary tumor to distant sites at early stage, which is characterized by disseminated tumor cells (DTCs). However, lack of direct evidence of partial localized PCa cells occurring epithelial-to-mesenchymal transition (EMT) and disseminating to distant sites (e.g bone marrow). In this study, we used luciferase labeled PCa cells to establish an EMT mouse model and to detect whether DTCs spread into the bone marrow. We observed tumor cells existing in mouse bone marrow when tumor grew subcutaneously at palpable stage. Studies also showed that ex vivo tumor cells exhibited increased proliferative, migratory, invasive and angiogenesis abilities. When compared ex vivo tumor cells with parental cells, hallmarks of EMT including E-cadherin, Vimentin, Snail, and ZO-1 were altered significantly. Specifically, the ex vivo tumor cells showed more mesenchymal properties. Angiogenesis markers, including VEGFR2, VEGFR3, MCP-3, I-TAC, I309, uPAR and GROα, were also increased in the ex vivo tumor cells. Intriguingly, MCP-1 expression was dramatically increased in those cells. Mechanistic analyses indicated that AP1 mediates PCa EMT and the appearance of DTCs via the Akt/mTOR pathway. This study may provide potential therapeutic targets and diagnostic biomarkers of PCa progression and metastasis.

3.
Oncol Rep ; 39(3): 1485-1493, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29344638

ABSTRACT

Nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies and is typically treated with radiotherapy and chemotherapy. Garcinone C, a natural compound isolated from Garcinia oblongifolia Champ., is a xanthone derivative with potential cytotoxic effects on certain cancers. However, there are limited studies regarding its effects on NPC cells, and its mechanism of action in NPC remains unknown. In the present study, we found that garcinone C significantly inhibited cell viability of the human NPC cell lines CNE1, CNE2, HK1 and HONE1. This inhibition was exerted in a time­ and dose­dependent manner. Flow cytometry demonstrated that garcinone C arrested the cell cycle at the S phase. Moreover, with 10 µM of high­dose garcinone C treatment, the cells exhibited necrotic morphology changes including cell swelling, rough endoplasmic reticulum degranulation, endoplasmic reticulum dilatation, mitochondrial swelling and vacuolar degeneration. In addition, we found that garcinone C stimulated the expression levels of ATR and 4E­BP1, while efficiently inhibiting the expression levels of cyclin B1, cyclin D1, cyclin E2, cdc2, CDK7 and Stat3. Collectively, the ability of garcinone C to inhibit NPC in growth in vitro suggested that garcinone C may be a novel agent for the management of NPC.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Carcinoma/pathology , Gene Expression Regulation, Neoplastic/drug effects , Nasopharyngeal Neoplasms/pathology , Phosphoproteins/metabolism , STAT3 Transcription Factor/metabolism , Xanthones/pharmacology , Adaptor Proteins, Signal Transducing/genetics , Apoptosis/drug effects , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , Biomarkers, Tumor , Carcinoma/drug therapy , Carcinoma/metabolism , Cell Cycle Proteins , Cell Proliferation/drug effects , Humans , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/metabolism , Phosphoproteins/genetics , STAT3 Transcription Factor/genetics , Tumor Cells, Cultured
4.
Sci Rep ; 7: 41656, 2017 01 30.
Article in English | MEDLINE | ID: mdl-28134352

ABSTRACT

Litchi (Litchi chinensisSonnnerat, Sapindaceae), known as Chinese Cherry, is a subtropical fruit tree originating from southern China. Litchi seed extracts have diverse pharmacological effects, including anticancer. However, its anticancer effects and mechanisms on prostate cancer have not been determined. In this study, we used n-butyl alcohol extract of Litchi seed (NLS) to treat prostate cancer PC3, DU145, RM1 and C4-2B cells. NLS induced a significant decrease in cell viability and clonogenic growth in a dose-dependent manner. NLS induced cell apoptosis and cell cycle G1/S phase arrest by inactivating Akt signaling pathway, which were associated with activation of mitochondrial caspase-dependent apoptotic cascades, up-regulation of cyclin-dependent kinase (CDK) inhibitors p21 and p27, and inhibition of correlated cyclin/CDK network. In addition, NLS treatment significantly decreased cell migration and invasion via phenotypic inversion of EMT, correlated with increased expression of E-cadherin and ß-catenin, and decreased expression of vimentin and snail, which is partially attributed to inhibiting Akt/GSK-3ß signaling pathway. Finally, PC3 xenograft nude mice treated with NLS in vivo showed a significant decrease in tumor size without toxicity. These findings suggest that NLS has potential for development into a safe and potent alternative therapy for prostate cancer patients.


Subject(s)
Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Epithelial-Mesenchymal Transition/drug effects , Litchi/chemistry , Plant Extracts/therapeutic use , Prostatic Neoplasms/drug therapy , Signal Transduction , Animals , Antineoplastic Agents/pharmacology , Cadherins/metabolism , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Cyclins/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Male , Mice , Mice, Nude , Plant Extracts/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Snail Family Transcription Factors/metabolism , Vimentin/metabolism
5.
Tumour Biol ; 36(11): 8811-8, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26058873

ABSTRACT

Nasopharyngeal carcinoma (NPC) is a common malignancy in southern China and Southeast Asia. NPC frequently metastasizes to the bone in advanced patients resulting in high mortality. The molecular mechanisms for NPC development and cancer-induced bone lesions are unclear. In this study, we firstly determined chemokine receptor CCR2 and CXCR6 expressions in clinical specimens and CNE2, SUNE1, CNE1, and HK1 cell lines. Then, we measured chemokine CCL2 and CXCL16 production in these NPC cell lines by ELISA. Expression levels of these chemokines and their receptors were observed to positively correlate with tumor aggressiveness. Furthermore, U0126 (MEK inhibitor) was used to treat these NPC cell lines. CCL2 and CXCL16 expression levels and cell proliferation were significantly inhibited by U0126 in a dose- and time-dependent manner. Finally, we collected conditioned medium (CM) from NPC cell cultures in the presence of U0126 treatment. When mouse bone marrow non-adherent cells were treated with the CM, the numbers of multinucleated osteoclast formation were dramatically diminished. These results indicate that MEK inhibitor diminishes NPC cell proliferation and NPC-induced osteoclastogenesis via modulating CCL2 and CXCL16 expressions. This study provides novel therapeutic targets such as CCL2/CCR2 and CXCL16/CXCR6 for advanced NPC patients.


Subject(s)
Chemokine CCL2/biosynthesis , Chemokines, CXC/biosynthesis , MAP Kinase Kinase Kinases/genetics , Nasopharyngeal Neoplasms/genetics , Receptors, Scavenger/biosynthesis , Animals , Bone Marrow Cells/drug effects , Butadienes/administration & dosage , Carcinoma , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Chemokine CCL2/genetics , Chemokine CXCL16 , Chemokines, CXC/genetics , Culture Media, Conditioned/pharmacology , Gene Expression Regulation, Neoplastic , Humans , MAP Kinase Kinase Kinases/antagonists & inhibitors , Mice , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/pathology , Nitriles/administration & dosage , Osteoclasts/drug effects , Osteoclasts/pathology , Protein Kinase Inhibitors/administration & dosage , Receptors, Scavenger/genetics
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