Context/Aims: Metabolic reprogramming and cellular plasticity drive tumorigenesis. However, how these cellular events collectively contribute to the oncogenic process is poorly understood. Epithelial-mesenchymal transition (EMT), a fundamental mechanism of cellular plasticity, is governed by the EMT transcription repressors such as Snail. In the present study, through establishment and characterization of inducible overexpression of Snail in A549 lung cancer cells, we aim to define the metabolic reprogramming in response to Snail in the EMT of lung cancer cells. Methods/Results: Our metabolomic analysis suggests that forced expression of Snail accompanied reduced diversion of glycolytic metabolites to the serine/glycine metabolic shunt, a critical metabolic branch that distributes glucose catabolic intermediates to the major anabolic pathways. Our gene expression profiling and molecular characterization revealed that Snail actively suppressed the expression of glycine decarboxylase (GLDC), a key enzyme on the serine/glycine metabolic shunt, through binding to an evolutionarily conserved E-box motif and thereby inhibiting the promoter of the GLDC gene. Besides, knockdown of GLDC led to a cellular function shift from proliferation to migration. Conclusion: This study has revealed a novel molecular link that integrates the serine/glycine metabolism with the Snail-mediated EMT program in cancer cells.
The ARF and INK4a genes are located on the CDKN2a locus, both showing tumor suppressive activity. ARF has been shown to monitor potentially harmful oncogenic signalings, making early stage cancer cells undergo senescence or programmed cell death to prevent cancer. Conversely, INK4a detects both aging and incipient cancer cell signals, and thus these two gene functions are different. The efficiency of detection of oncogenic signals is more efficient for the for the former than the latter in the mouse system. Both ARF and INK4a genes are inactivated by gene deletion, promoter methylation, frame shift, aberrant splicing although point mutations for the coding region affect only the latter. Recent studies show the splicing alterations that affect only ARF or both ARF and INK4a genes suggesting that ARF is inactivated in human tumors more frequently than what was previously thought. The ARF gene is activated by E2Fs and Dmp1 transcription factors while it is repressed by Bmi1, Tbx2/3, Twist1, and Pokemon nuclear proteins. It is also regulated at protein levels by Arf ubiquitin ligase named ULF, MKRN1, and Siva1. The prognostic value of ARF overexpression is controversial since it is induced in early stage cancer cells to eliminate pre-malignant cells (better prognosis); however, it may also indicate that the tumor cells have mutant p53 associated with worse prognosis. The ARF tumor suppressive protein can be used as a biomarker to detect early stage cancer cells as well as advanced stage tumors with p53 inactivation.
The interaction between the bone marrow microenvironment and leukemia cells enhances cell adhesion-mediated signals that can promote malignant hematopoietic cell survival and change normal hematopoiesis. Integrins, on the surface of leukemia cells, are involved in this interaction and mediate cell adhesion to integrin receptors of other cells and the extracellular matrix. Studies show that inhibition of several integrins affects leukemia cell migration or survival as well as sensitivity to chemotherapy. This review focuses on the expression and role of key arginine–glycine–aspartate acid (RGD)-binding (αvβ3, α5β1, αIIbβ3) and non-RGD-binding (α2β1, α4β1, α6β1, and αLβ2) integrins on leukemia cells and in the leukemia microenvironment and their potential targeting in leukemia treatment.
Objective: The most challenging problem in oral cancer is late monitoring and disease spread (metastasis). The study aimed to simultaneously evaluate phosphorylated epidermal growth factor receptor (pEGFR), truncated E-cadherin protein, and matrix metalloproteinases (MMPs) in patients with oral cancer. Methodology: pEGFR and truncated E-cadherin protein were measured from 25 paired tissues by ELISA and Western blot, respectively. Plasma MMPs levels were studied by gelatin zymography from 100 controls and 100 patients with oral cancer. The results revealed significant higher expression of pEGFR and truncated E-cadherin protein in malignant oral cancer tissues as compared to adjacent normal. Plasma MMPs were significantly elevated in patients with oral cancer as compared to the controls. An increase in the levels of pEGFR and truncated E-cadherin protein was observed in advanced and metastatic disease as compared to early and nonmetastatic disease. The levels of MMPs were increased in advanced disease as compared to early disease. Kaplan–Meier's survival analysis indicated that elevated expression of pEGFR, truncated E-cadherin protein, active MMP-2, pro MMP-9, total MMP-2, and total MMP-9 has reduced the overall survival. Conclusion: Simultaneous elevation of pEGFR, truncated E-cadherin protein, and MMPs indicated its role in oral carcinogenesis. Further combination therapies targeting these markers might help in combating oral cancer.
INTRODUCTION:The src inhibitor Dasatinib has been widely studied as an anti-metastatic agent. The aims of this study were to examine the effect of Src inhibition on the metastatic potential of the 4T1 murine mammary carcinoma. CONTEXT:Src is a non-receptor tyrosine kinase well-known to contribute to the metastatic potential of tumour cells. It does so through alteration of signalling pathways important to metastasis. Elevated levels of Src are common in many cancer types, and have been correlated with tumour progression and poor patient prognosis. AIMS:This study examined whether disruption of the Src signalling pathway could inhibit metastases formation. SETTINGS AND DESIGN:The Src inhibitor Dasatinib was evaluated in vitro and in vivo using the highly metastatic 4T1 murine mammary adenocarcinoma cell line. METHODS AND MATERIAL:In vitro assays included growth curve, western blot, migration, and invasion assays. In vivo assays included intradermal and tail vein injection models. STATISTICAL ANALYSIS USED:In vitro data were analysed using one-way ANOVA with Dunnett's multiple comparisons in GraphPad Prism 6.0. In vivo data were analysed using GraphPad Prism 6.0, using the Wilcoxon matched pairs test. RESULTS:Dasatinib is effective at inhibiting in vitro phosphorylation of Src, migration and invasion in the 4T1 cell line, as well as angiogenesis in vivo. In vitro treatment with Dasatinib impaired the metastatic ability of tumour cells as assessed by a tail vein injection model. However, both the syngeneic BALB/c and the athymic nu/nu mice receiving oral doses of the drug developed significantly higher numbers of 4T1 lung metastases. This effect was not seen in a different breast carcinoma cell line, the MDA-MB-231-4175-LM2, nor was this effect seen in the murine fibrosarcoma KHT cell line. CONCLUSIONS:The 4T1 cell line is not an appropriate model to study Src inhibition.
