No abstract

RACK1 is a highly conserved intracellular adaptor protein with significant homology to Gβ and was originally identified as the anchoring protein for activated protein kinase C. In the past 20 years, the number of binding partners and validated cellular functions for RACK1 has increased, which facilitates clarification of its involvement in different biological events. In this review, we will focus on its role in cancer, summarizing its aberrant expression, pro- or anti-oncogenic effects and the underlying mechanisms in various cancers.

A series of 1,2-diarylcyclopentene methyl sulfones and sulfonamides have been shown to be remarkably potent and selective cyclooxygenase-2 (COX-2) inhibitors. The methyl sulfone analogs 7 showed excellent COX-2 activity, with IC50s ranging from 0.003 (7f,n) to 0.87 (7o) microM. In addition, most analogs of 7 showed no activity (IC50 > 100 microM) against the COX-1 enzyme. Replacement of the methyl sulfone moiety with a sulfonamide group gave a slightly more potent (typically 2-5-fold) but less selective COX-2 inhibitor, mainly due to an increase (20- > 100-fold) in COX-1 activity. However, in vitro COX-1/COX-2 selectivity for the sulfonamides 8 could be increased in many cases by simply incorporating a substituent at the 3-position of the phenyl group. Furthermore, in vitro selectivity increased with the size and number of substituents, as demonstrated in the selectivity trend of 8k (8000) > 8j (1900) > 8i (500) > 8h (100). More importantly, the sulfonamide COX-2 inhibitors showed greatly enhanced oral activity in the rat model of established adjuvant-induced arthritis, with inhibition values of 79.0% (8a), 81.5% (8c), and 83.0% (8g) at 1 mg/kg. On the basis of its overall biological profile, sulfonamide 8c was evaluated as a potential clinical candidate, displaying an ED50 of 22 mpk in the rat carrageenan-induced paw edema model and an ED50 of 0.16 mpk in the rat established adjuvant-induced arthritis model with no indication of gastrointestinal toxicity in rats and mice at 200 mpk. In addition, a preparative-scale synthetic route to sulfonamide 8c has been developed.

Through clever design of an oligonucleotide probe, the molecular beacon (MB), protein – DNA interactions can be studied and proteins quantified. The principle involves a design in which the fluorophore (F) of the MB is quenched by intramolecular interaction with a quenching group (Q) in close proximity. This quenching is relieved by the interaction of the molecular beacon with a single‐stranded DNA binding protein (SSB). As a result, fluorescence is restored and can be monitored. This approach could be developed into a powerful method for directly monitoring protein production in living cells and organs.

Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands play important roles in nervous system development. Recently, they have been implicated in tumorigenesis of different cancers. In this study, we showed that the expression of ephrinA5 was dramatically downregulated in primary gliomas compared with normal tissues. Forced expression of ephrinA5 reduced tumorigenicity of human glioma U373 cells. Epidermal growth factor receptor (EGFR), which frequently acts as an oncoprotein in glioma, was greatly decreased in ephrinA5-transfected glioma cells, and the two molecules exhibited a mutually exclusive expression pattern in primary glioma samples. We found that ephrinA5 enhanced c-Cbl binding to EGFR, thus promoted ubiquitylation and degradation of the receptor. Either ephrinA5-Fc or EphA2-Fc treatment simulating bidirectional signaling of Eph/ephrin system resulted in EGFR decrease. This study discovered that ephrinA5 acted as a tumor suppressor in glioma, and its negative regulation of EGFR contributed to the suppressive effects. In addition to identifying a novel mechanism underlying tumor suppressor activity of ephrinA5, we also showed cross-talk between different receptor tyrosine kinase families in glioma. These findings may improve therapeutic strategies for glioma.

There is increasing evidence that both endogenous and exogenously ingested estrogens play a primary role in sporadic breast cancer causation. To establish further that solely estrogen-induced mammary oncogenesis in female ACI rats is an estrogen receptor (ER )-driven process, we show for the first time that concomitant treatment with the antiestrogen, tamoxifen citrate (TAMc), completely prevents the induction of 17 -estradiol (E 2 )-induced mammary gland tumors (MGTs). This finding is also supported by the reduced mammary gland (MG) lobulo-alveolar development and proliferative activity observed in TAMc+E 2 -treated animals compared with MGs from animals treated with E 2 alone. These data also correlated with a marked decrease in the number of MG cells expressing ER and progesterone receptor (PR) in immunostained MG tissue sections from TAMc+E 2 -treated animals. Additionally, a marked decline in the level of expression of ER 47, 56 and 66 kDa forms, and PR-A and PR-B was seen in TAMc+E 2 -treated MGs, compared with MGs treated solely with E 2 . Thus, both ER and PR MG profiles in TAMc+E 2 -treated rats essentially revert to their respective receptor profiles seen in untreated control and TAMc-alone-treated rats. The presence of 56 and 54 kDa isoforms in chronically E 2 -treated MGs and in MGTs respectively may contribute to fostering the enhanced E 2 -dependent growth response of both precursor and frank MGT epithelial cells. These findings are consistent with an ER /PR-mediated MG cell proliferation, a prerequisite for generating the high frequency of chromosomal instability seen in E 2 -induced ductal carcinomas in situ and primary MGTs in female ACI rats reported by us previously.

Objective: Spinal cord edema contributes to the pathophysiological mechanisms underlying spinal cord injury (SCI) and is associated with functional recovery after SCI. Early myelotomy may be a promising surgical intervention for reducing SCI-induced edema. However, it remains unclear whether myelotomy can reduce SCI-induced edema. In addition, aquaporin-4 (AQP4) and aquaporin-9 (AQP9) have important roles in the regulation of water homeostasis. Here, we aimed to determine the effects of myelotomy on AQP4 and AQP9 expression and spinal cord edema in a rat model of moderate SCI. Methods: Rats were randomly assigned to three groups: the sham control group (n = 22) receiving laminectomy alone; the contusion group (n = 44) receiving laminectomy plus contusion; and the myelotomy group (n = 44) receiving laminectomy plus contusion followed by myelotomy at 24 h. Functional recovery was estimated by the open-field and inclined plane tests. Spinal cord edema was determined by measuring the water content. The expression of AQP4 and AQP9 was determined by western blot. Results: Compared with the contusion group, myelotomy significantly improved the Basso, Beattie and Bresnahan scores in the open-field test and resulted in a higher mean angle value in the incline plane test. Myelotomy significantly reduced SCI-induced edema at 4 and 6 days after SCI, which was accompanied by downregulation of AQP4 and AQP9 expression. Conclusion: Myelotomy improves locomotor function, reduces edema in rats with SCI and is associated with decreased expression of AQP4 and AQP9.

In patients with nasopharyngeal carcinoma treated with radiotherapy, the severity and incidence of radiation-induced sensorineural hearing loss increased with time, especially at high frequencies. This hearing impairment may be due to changes in the cochlea and/or the retrocochlear auditory pathway.