Molecular and cellular pharmacology最新文献

Glutamate AMPA receptors (AMPAR) in the nucleus accumbens have an important role in cocaine-induced neuroadaptations. Neuronal pentraxins function in the extracellular matrix to bind AMPAR. Three neuronal pentraxins have been described Narp, NP1 and NPR. Narp and NP1 cluster AMPA receptors, while NPR contributes to removing AMPA receptors during mGluR-dependent long-term depression. We recently demonstrated that each pentraxin contributes to cocaine-induced neuroadaptations in a way that is consistent with its role in AMPAR clustering and trafficking. Thus, Narp and NP1 deletion promoted cocaine-induced place preference and showed blunted AMPA induced locomotion after cocaine withdrawal. In contrast NPR deletion augmented the AMPA response and was without effect on place preference. Consistent with reduced AMPA responsiveness after chronic cocaine in Narp KO mice, GluR1 was reduced in the postsynaptic density (PSD) fraction of Narp KO mice withdrawn from cocaine. These findings will be discussed in light of recent data showing that rats withdrawn from cocaine have marked deficits in developing long-term potentiation and long-term depression.

Thapsigargin (TG) is a sesquiterpen lactone that inhibits the endoplasmic reticulum (ER) calcium ATPases to disrupt calcium homeostasis and consequently induces ER stress. We have previously reported that TG induces apoptosis by engaging the death receptor 5 (DR5) and the intrinsic pathways. Second mitochondrial-derived activator (Smac) is an important modulator of apoptosis that induces activation of caspases by antagonizing inhibitors of apoptosis (IAPs). In this study, we have utilized Smac-proficient and -deficient human colon cancer cells to investigate the effects of Smac deficiency during ER-stress-induced apoptosis. Our results indicate that Smac deficiency considerably affects ER stress-induced apoptosis in human colon cancer cells. For example, ER stress inducing agent TG upregulates DR5, and activates caspases 3, 9 and 8 in Smac-proficient cells. In Smac-deficient cells, although TG-induced DR5 upregulation is not affected, activation of caspases 3, 9 and 8 is affected. Smac deficiency also affects TG-induced cytochrome c release from mitochondria into cytosol suggesting the existence of a potential cross-talk between Smac and cytochrome c. Thus, our results indicate that ER stress-induced apoptosis also engages Smac for transduction of apoptotic signals in human colon cancer cells and that a potential feedback signaling between Smac and cytochrome c appears to modulate the intrinsic pathway of apoptosis.

Organic selenium compounds are known to prevent certain cancers although mechanisms may be complex. A widely-held view is that selenium compounds can induce apoptosis in cancer cells, or more precisely, in aberrant cells that are undergoing clonal evolution somewhere along the carcinogenesis process. There are at least 20 different selenium compounds, inorganic as well as organic, that have been used in various published studies. Extrapolation between studies should therefore be undertaken with caution. Similarly, it will be important to ascertain the physiological relevance of the selenium concentrations used in some studies. While cancer prevention by selenium is well-established, recently, organic selenium in the form of pure seleno-L-methionine (SeMet) has been used in combination with cancer chemotherapy drugs. SeMet can induce a DNA repair response in some cell types including bone marrow. Cancer cells generally lack a SeMet-inducible DNA repair response. Thus, SeMet appears to selectively regulate a DNA repair pathway and thereby potentially alter responses to cancer chemotherapy drugs. The specific pathway implicated, nucleotide excision DNA repair (NER) is required for repair of cisplatin or carboplatin DNA damage relevant to chemotherapy. Moreover, some studies have implicated NER as a factor in carcinogenesis processes. Thus, the capacity of SeMet to selectively regulate NER may prove useful in both therapeutic and preventive contexts.

The transforming growth factor (TGF) β signaling pathway is involved in many cellular processes including proliferation, differentiation, adhesion, motility and apoptosis. The loss of TGFβ signaling occurs early in carcinogenesis and its loss contributes to tumor progression. The loss of TGFβ responsiveness frequently occurs at the level of the TGFβ type II receptor (TGFβRII) which has been identified as a tumor suppressor gene (TSG). In keeping with its TSG role, the loss of TGFβRII expression is frequently associated with high tumor grade and poor patient prognosis. Reintroduction of TGFβRII into tumor cell lines results in growth suppression. Mutational loss of TGFβRII has been characterized, particularly in a subset of colon cancers with DNA repair enzyme defects. However, the most frequent cause of TGFβRII silencing is through epigenetic mechanisms. Therefore, re-expression of TGFβRII by use of epigenetic therapies represents a potential therapeutic approach to utilizing the growth suppressive effects of the TGFβ signaling pathway. However, the restoration of TGFβ signaling in cancer treatment is challenging because in late stage disease, TGFβ is a pro-metastatic factor. This effect is associated with increased expression of the TGFβ ligand. In this Review, we discuss the mechanisms associated with TGFβRII silencing in cancer and the potential usefulness of histone deacetylase (HDAC) inhibitors in reversing this effect. The use of HDAC inhibitors may provide a unique opportunity to restore TGFβRII expression in tumors as their pleiotropic effects antagonize many of the cellular processes, which mediate the pro-metastatic effects associated with increased TGFβ expression.

The Aryl-hydrocarbon receptor (AHR) is a ligand activated transcription factor involved in xenobiotic metabolism. Most of the toxic effects of halogenated and non-halogenated polycyclic aromatic hydrocarbons (HAHs and PAHs respectively) are mediated by the AHR. For the AHR, a number of intra and interspecies differences exist in terms of responsiveness to the prototypical AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Interspecies differences in AHR ligand binding affinity has been shown to be linked to contrasting TCDD tolerance between species and among inbred strains of mice expressing different AHR alleles. Compared to the human AHR (hAHR), the mouse AHR(b) (mAHR(b)) has a ~10 fold higher affinity for typical AHR ligands. Using a transgenic humanized mouse model that expresses hAHR protein specifically in the liver, we have discovered that for certain ligands, such as indirubin, the hAHR exhibits higher relative ligand binding affinity and responsiveness compared to the mAHR(b). These findings may potentially influence the ongoing search for endogenous hAHR ligands and expand our understanding of the unique physiological role of the hAHR.

TGF-β signaling regulates several different biological processes involving cell-growth, differentiation, apoptosis, motility, angiogenesis, epithelial mesenchymal transition and extracellular matrix production that affects embryonic development and pathogenesis of various diseases, including cancer, its effects depending on the cellular context and physiological environment. Growth suppression mediated by TGF-β signaling often associated with inhibition of c-myc, cdks and induction of p15, p27, Bax and p21. Despite its growth inhibitory effect, in certain conditions TGF-β may act as a promoter of cell proliferation and invasion. Loss of responsiveness to growth suppression by TGF-β due to mutation or loss of TGF-beta type II receptor (TβRII) and Smad4 in several different cancer cells are reported. In addition, TGF-β binding to its receptor activates many non-canonical signaling pathways. Radiation induced TGF-β is primarily involved in normal tissue injury and fibrosis. Seminal studies from our group have used radio-adjuvant therapies, involving classical components of the pathway such as TβRII and SMAD4 to overcome the growth promoting effects of TGF-β. The main impediment in the radiation-induced TGF-β signaling is the induction of SMAD7 that blocks TGF-β signaling in a negative feedback manner. It is well demonstrated from our studies that the use of neutralizing antibodies against TGF- β can render a robust radio-resistant effect. Thus, understanding the functional interactions of TGF-β signaling components of the pathway with other molecules may help tailor appropriate adjuvant radio-therapeutic strategies for treatment of solid tumors.

Cryoablation is one of the established treatment modalities for prostate cancer management. Although, it is target specific, it may still lead to damage to the nerve fibers around the prostate tumor. In this study, by directly exposing the co-cultures of prostate cancer cells, PC-3 and Schwann cell-Dorsal Root Ganglion neuron (SC-DRG) to cryo-shock and by exposing SC-DRG to cryo-shock conditioned media (CSCM) obtained from PC-3 cells, robust neuro-protective effects were observed. Since this neuro-protective effect originated from cryotherapy-treated PC-3 cells, the presence of putative factors secreted by PC-3 cells in the medium following cryo-shock was analyzed. Using human cytokine antibody array analysis, differential release of cytokines in CSCM was observed with induced release of cytokines involved in neuro-protection like IL-1α, MIP-4, MIP-5, Leptin, IL-15 and ICAM-1 with simultaneous inhibition of TNFRI and TNFRII that are implicated in killing of nerve cells. Further, using Matrix Assisted Laser Desorption/Ionization-Time Of Flight (MALDI-TOF) sequencing, two proteins were identified namely, CypA (cyclophilin A) and NM23 (nonmetastatic protein 23) in the CSCM. CypA functions as a mediator of intracellular as well as extracellular neuro-protective mechanisms and NM23 has been implicated as a potential suppressor protein of tumor metastasis. Thus, this study revealed the presence of factors in CSCM that has the potential to protect normal neuronal cells and suppress metastasis.

Inflammation is closely linked to cancer, and many anti-cancer agents are also used to treat inflammatory diseases, such as rheumatoid arthritis. Moreover, chronic inflammation increases the risk for various cancers, indicating that eliminating inflammation may represent a valid strategy for cancer prevention and therapy. This article explores the relationship between inflammation and cancer with an emphasis on epidemiological evidence, summarizes the current use of anti-inflammatory agents for cancer prevention and therapy, and describes the mechanisms underlying the anti-cancer effects of anti-inflammatory agents. Since monotherapy is generally insufficient for treating cancer, the combined use of anti-inflammatory agents and conventional cancer therapy is also a focal point in discussion. In addition, we also briefly describe future directions that should be explored for anti-cancer anti-inflammatory agents.