Molecular and cellular pharmacology最新文献

The normal function of the extrinsic apoptotic pathway is to mediate apoptosis. Thus, this pathway is generally recognized to be critical in host immune surveillance against cancer. However, many studies have suggested that some key components in this pathway including Fas, death receptor 5 (DR5), Fas-associated death domain (FADD) and caspase-8 may contribute to cancer growth or metastasis. Our recent study on DR5 and caspase-8 expression in human head and neck cancer tissues indicate that high caspase-8 either alone or along with high DR5 in tumor tissue from patients with lymph node metastasis is significantly associated with poor disease-free survival and overall survival, suggesting that these proteins may be involved in positive regulation of cancer metastasis. Thus, efforts should be made to better understand the role of the death receptor 5/FADD/caspase-8 death signaling in regulation of cancer metastasis.

The disorder of microRNAs (miRNAs) often referred as 'micromanagers of gene expression' has been implicated with a vast array of neoplasmthe discovery establishes an important connection with the etiology, diagnosis and potential therapy of human cancer. Indeed, the wide range of profiling studies enabled to create miRNA signatures of solid tumors as well as cancers of blood origin. MiRNAs have been observed to play a significant role in the regulation of gene expression-a critical aspect of many biological processes, including cell development, differentiation, apoptosis and proliferation. The differential expression levels of miRNAs in tumors and their normal counterpart have enabled scientists to designate their roles as oncomir or tumor suppressor. Interestingly, the diminishment of oncogenic or enhanced levels of tumor suppressor miRNAs (antagomirs) have been reported to modulate the sensitivity of cancer cells to anticancer agents. To the other end, carcinogenic chemicals either possess the ability of silencing beneficial tumor suppressive miRNAs or maintain the augmented levels of their oncogenic counterpart. In this article we provide a comprehensive overview on the modulation of these "micromanaging oligos" by cancer causing as well as cancer preventing agents.

Prostate cancer (PCa) is the most common non-skin cancer among men. Currently available diagnostic tests for PCa are inadequate in terms of low specificity and poor sensitivity. microRNAs offer a hope to overcome these drawbacks by virtue of their cancer specific expression and high stability. They can readily be detected and quantified in frozen and as well as formalin-fixed paraffin-embedded tissues. Observation of circulating miRNA in serum/plasma samples and other body fluids holds a promise to quickly move from research and provide a biomolecule of clinical relevance and an improvement over presently available biomarkers. This review highlights the potential role of circulating miRNAs as molecular markers for cancer and as targets for therapeutic manipulation. Further, this review summarizes the current understanding of various circulating miRNA with respect to prostate cancer. To conclude, circulating miRNAs are an active area of current investigation and holds promise to serve a wide range of clinical applications and unwrap a new era in cancer diagnosis and therapeutics.

To improve the effectiveness of anti-cancer therapies, it is necessary to identify molecular targets that are essential to a tumor cell but dispensable in a normal cell. Increasing evidence indicates that the transcription factor STAT3, which regulates the expression of genes controlling proliferation, survival, and self-renewal, constitutes such a target. Recently it has been found that STAT3 can associate with the cytoskeleton. Since many of the tumors in which STAT3 is activated, such as breast cancer and ovarian cancer, are responsive to drugs that target microtubules, we examined the effect of these compounds on STAT3. We found that microtubule stabilizers, such as paclitaxel, or microtubule inhibitors, such as vinorelbine, decrease the activating tyrosine phosphorylation of STAT3 in tumor cells and inhibit the expression of STAT3 target genes. Paclitaxel decreases the association between STAT3 and microtubules, and appears to decrease STAT3 phosphorylation through induction of a negative feedback regulator. The cytotoxic activity of paclitaxel in breast cancer cell lines correlates with its ability to decrease STAT3 phosphorylation. However, consistent with the necessity for expression of a negative regulator, treatment of resistant MDA-MB-231 cells with the DNA demethylating agent 5-azacytidine restores the ability of paclitaxel to block STAT3-dependent gene expression. Finally, the combination of paclitaxel and agents that directly target STAT3 has beneficial effects in killing STAT3-dependent cell lines. Thus, microtubule-targeted agents may exert some of their effects by inhibiting STAT3, and understanding this interaction may be important for optimizing rational targeted cancer therapies.