Hypoxia-mediated apoptosis in oral carcinoma cells occurs via two independent pathways

BACKGROUND: We are attempting to elucidate the mechanism of apoptotic cell death induced by hypoxia in oral cancer cells. Since hypoxia can render solid tumors more resistant to radiation and chemotherapy, understanding the pathways involved in hypoxia-induced apoptosis of oral cancer cells would be of significant therapeutic value. RESULTS: Here we showed that oral cancer cells from primary tumor and lymph node metastasis undergo apoptosis after 24 to 48 h of hypoxia. During hypoxic growth, an increase in caspase-3 proteolytic activity was observed, accompanied by the cleavage of PARP (poly (ADP-ribose) polymerase) indicative of caspase activity. In addition, hypoxic stress also lead to activation of caspase-8, -9, and -10 but not -1, elicited the release of cytochrome C into the cytosol, and resulted in internucleosomal DNA fragmentation. CONCLUSION: These results show that hypoxia-induced apoptosis in oral carcinoma cell lines relies on both intrinsic (mitochondrial) and extrinsic (cell death receptor mediated) pathways. This novel evidence will assist in designing more efficient combination chemotherapy approaches as promising strategy for the treatment of oral cancers

Evolving 'omics' technologies for diagnostics of head and neck cancer

Squamous cell carcinoma of head and neck (SCCHN) is the sixth most common malignancy and is a major cause of cancer morbidity and mortality worldwide. As with most solid cancers, the cure rate for SCCHN is excellent if tumors are diagnosed early in the course of the disease. Early diagnosis of cancer remains difficult because of the lack of specific symptoms in early disease as well as the limited understanding of etiology and oncogenesis. Advances in proteomics and genomics contribute to the understanding of the pathophysiology of neoplasia, cancer diagnosis and anticancer drug discovery. The powerful 'omics' technologies have opened new avenues towards biomarker discovery, identification of signaling molecules associated with cell growth, cell death, cellular metabolism and early detection of cancer. Analysis of tumor-specific omics profiles provided a unique opportunity to diagnose, classify, and detect malignant disease; to better understand and define the behavior of specific tumors; and to provide direct and targeted therapy. These technologies however still require integration and standardization of techniques and validation against accepted clinical and pathologic parameters. This article provides a summary of technologies, potential clinical applications, and challenges of omics in head and neck cancer

RAD51 as a potential biomarker and therapeutic target for pancreatic cancer

Chemotherapy is a very important therapeutic strategy for cancer treatment. The failure of conventional and molecularly targeted chemotherapeutic regimes for the treatment of pancreatic cancer highlights a desperate need for novel therapeutic interventions. Chemotherapy often fails to eliminate all tumor cells because of intrinsic or acquired drug resistance, which is the most common cause of tumor recurrence. Overexpression of RAD51 protein, a key player in DNA repair/recombination has been observed in many cancer cells and its hyperexpression is implicated in drug resistance. Recent studies suggest that RAD51 overexpression contributes to the development, progression and drug resistance of pancreatic cancer cells. Here we provide a brief overview of the available pieces of evidence in support of the role of RAD51 in pancreatic tumorigenesis and drug resistance, and hypothesize that RAD51 could serve as a potential biomarker for diagnosis of pancreatic cancer. We discuss the possible involvement of RAD51 in the drug resistance associated with epithelial to mesenchymal transition and with cancer stem cells. Finally, we speculate that targeting RAD51 in pancreatic cancer cells may be a novel approach for the treatment of pancreatic cancer. (C) 2011 Elsevier B.V. All rights reserved

Cigarette smoke condensate increases cathepsin-mediated invasiveness of oral carcinoma cells

Cigarette smoke, which contains several carcinogens known to initiate and promote tumorigenesis and metastasis, is the major cause of oral cancer. Lysosomal cathepsin proteases play important roles in tumor progression, invasion and metastasis. In the present work we investigated the effects of cigarette smoke condensate (CSC) on cathepsin (B, D and L) expression and protease-mediated invasiveness in human oral squamous cell carcinoma (OSCC) cells. Our results show that treatment of OSCC cells (686Tu and 101A) with CSC activated cathepsins B, D and L in a dose-dependent manner. Both expression and activity of these cathepsins were up-regulated in CSC-exposed versus non-exposed cells. Although cathepsin L had the lowest basal level, it had the highest induction in exposed cells compared to cathepsins B and D. Suppression of CSC-induced cathepsin B and L activities by specific chemical inhibitors decreased the invasion process, suggesting that these proteases are involved in the invasion process. Overall, our results indicate that CSC activates cathepsin B and L proteolytic activity and enhances invasiveness in OSCC cells, a response that may play a role in CSC-mediated tumor progression and metastasis dissemination

Using genomics to develop novel antibacterial therapeutics

As the genomics era matures, the availability of complete microbial genome sequences is facilitating computational approaches to understand bacterial genomes and DNA structure/function relationships. From the genome of pathogens, we can derive invaluable information on potential targets for new antimicrobial agents. Advancements in high-throughput 'omics' technologies and the availability of multiple isolates of the same species have significantly changed the time frame and scope for identifying novel therapeutic targets. This article aims to discuss selected aspects of the bacterial genome, and advocates 'omics'-based techniques to advance the discovery of new therapeutic targets against extracellular bacterial pathogens

Pancreatic Cancer Stem Cells in Tumor Progression, Metastasis, Epithelial-Mesenchymal Transition and DNA Repair

Pancreatic cancer is an aggressive solid malignancy with poor response to therapy and the subsequent dismal survival rate has remained a hallmark of this disease. There is evidence to indicate that pancreatic cancer is initiated and propagated by cancer stem cell (CSC)s. The CSC population is defined by its tumor initiating capacity and has been shown to be invasive or metastatic. Loss of genome stability is a hallmark of cancer with DNA repair enzymes aiding in maintenance of stability. The potential to assess the risk of cancer development lies in careful determination of one’s capacity in nurturing genome stability. DNA repair genes are over expressed in CSCs and both pancreatic CSCs and invasive cells in turn provide greater DNA damage response and repair mechanisms. Pancreatic tumor-initiating cells as well as invasive cells have a large number of genes related to DNA repair. RAD51, the key player in the recombinational repair of damaged DNA might act as a critical mediator of efficient DNA repair mechanisms of CSCs. We update here the current research results regarding CSCs in pancreatic cancer progression, metastasis and discuss the DNA repair mechanism in pancreatic CSCs

Transcriptomics, proteomics and interactomics: unique approaches to track the insights of bioremediation

Microbial mediated bioremediation has a great potential to effectively restore contaminated environment, but the lack of information about factors regulating the growth and metabolism of various microbial communities in polluted environment often limits its implementation. Newly seeded techniques such as transcriptomics, proteomics and interactomics offer remarkable promise as tools to address longstanding questions regarding the molecular mechanisms involved in the control of mineralization pathways. During mineralization, transcript structures and their expression have been studied using high-throughput transcriptomic techniques with microarrays. Generally however, transcripts have no ability to operate any physiological response; rather, they must be translated into proteins with significant functional impact. These proteins can be identified by proteomic techniques using powerful two-dimensional polyacrylamide gel electrophoresis (2-DE). Towards the establishment of functional proteomics, the current advances in mass spectrometry (MS) and protein microarrays play a central role in the proteomics approach. Exploring the differential expression of a wide variety of proteins and screening of the entire genome for proteins that interact with particular mineralization regulatory factors would help us to gain insights into bioremediation

Proteomics: a strategy to understand the novel targets in protein misfolding and cancer therapy

Proteins carry out important functions as they fold themselves. Protein misfolding occurs during different biochemical processes and may lead to the development of diseases such as cancer, which is characterized by genetic instability. The cancer microenvironment exposes malignant cells to a variety of stressful conditions that may further promote protein misfolding. Tumor development and progression often arises from mutations that interfere with the appropriate function of tumor-suppressor proteins and oncogenes. These may be due to alteration of catalytic activity of the protein, loss of binding sites for effector proteins or alterations of the native folded protein conformation. Src family kinases, p53, mTOR and C-terminus of HSC70 interacting protein (CHIPs) are some examples associated with protein misfolding and tumorigenesis. Molecular chaperones, such as heat-shock protein (HSP)70 and HSP90, assist protein folding and recognize target misfolded proteins for degradation. It is likely that this misfolding in cancer is linked by common principles, and may, therefore, present an exciting possibility to identify common targets for therapeutic intervention. Here we aim to review a number of examples that show how alterations in the folding of tumor-suppressor proteins or oncogenes lead to tumorigenesis. The possibility of targeting the targets to repair or degrade protein misfolding in cancer therapy is discussed