Advances in Targeting the Epidermal Growth Factor Receptor Pathway by Synthetic Products and Its Regulation by Epigenetic Modulators As a Therapy for Glioblastoma.

Glioma is the most common primary tumor of the nervous system, and approximately 50% of patients exhibit the most aggressive form of the cancer, glioblastoma. The biological function of epidermal growth factor receptor (EGFR) in tumorigenesis and progression has been established in various types of cancers, since it is overexpressed, mutated, or dysregulated. Its overexpression has been shown to be associated with enhanced metastatic potential in glioblastoma, with EGFR at the top of a downstream signaling cascade that controls basic functional properties of glioblastoma cells such as survival, cell proliferation, and migration. Thus, EGFR is considered as an important therapeutic target in glioblastoma. Many anti-EGFR therapies have been investigated both in vivo and in vitro, making their way to clinical studies. However, in clinical trials, the potential efficacy of anti-EGFR therapies is low, primarily because of chemoresistance. Currently, a range of epigenetic drugs including histone deacetylase (HDAC) inhibitors, DNA methylation and histone inhibitors, microRNA, and different types of EGFR inhibitor molecules are being actively investigated in glioblastoma patients as therapeutic strategies. Here, we describe recent knowledge on the signaling pathways mediated by EGFR/EGFR variant III (EGFRvIII) with regard to current therapeutic strategies to target EGFR/EGFRvIII amplified glioblastoma.

Cathepsin O is involved in the innate immune response and metamorphosis of Antheraea pernyi.

Cathepsins are key members of mammalian papain-like cysteine proteases that play an important role in the immune response. In this study, a fragment of cDNA encoding cathepsin O proteinase (ApCathepsin O) was cloned from Antheraea pernyi. It contains an open reading frame of 1170bp and encodes a protein with 390 amino acid residues, including a conserved I29 inhibitor domain and a peptidase C1A (clan CA of cysteine proteases, papain family C1 subfamily) domain. Comparison with other previously reported cathepsin O proteins showed identity ranging from 45% to 79%. Quantitative real-time PCR (qRT-PCR) and Western blot analysis revealed that ApCathepsin O was highly expressed in the fat body; furthermore, the high expression during the pupal stage indicated that it might be involved during metamorphosis. After exposure to four different heat-killed pathogens (Escherichia coli, Beauveria bassiana, Micrococcus luteus, and A. pernyi nucleopolyhedrovirus), the expression levels of ApCathepsin O mRNA significantly increased and showed variable expression patterns. This indicates that ApCathepsin O is potentially involved in the innate immune system of A. pernyi. Interestingly, ApCathepsin O expression was upregulated after 20-hydroxyecdysone (20E) injection, which suggested that it might be regulated by 20E. In conclusion, ApCathepsin O is a protease that may play an important role in the innate immune response and metamorphosis of A. pernyi.