Editorial [Hot topic: Novel Proteins and Pathways as Anti-Cancer Therapeutic Targets (Guest Editor: Q. Ping Dou)]

Cell numbers are regulated by a balance between proliferation and apoptosis (programmed cell death), and an accurate coordination between these two processes are essential for maintaining cellular homeostasis. However, dysregulation of proliferation and cell death processes are hallmarks that distinguish cancer from normal cells. In recent years, a number of proteins and pathways have been identified to be essential for maintaining the cell growth-death balance or for the development and progression of several human malignancies. These proteins and pathways therefore represent novel therapeutic targets for anticancer drug discovery. This special issue will focus on several “oncoproteins” (the proteins with tumor-inducing ability; including: Notch signaling pathway proteins, the Mammalian Target of Rapamycin/ mTOR, Phosphoinositide 3-Kinases/ PI3Ks, Epidermal Growth Family Receptor/ EGFR, and androgen receptor/ AR) or protein complexes (the 26S proteasome as an example) and “tumor suppressor proteins” (such as Moesin-ezrin-radixin-like protein/ Merlin). The selected articles highlight these proteins and their structures, folding, mutations, interactions with cofactors or hormones, cellular functions, and regulations by signal transduction, as well as crosstalk between some of these pathways. Furthermore, results of pharmaceutical or peptide-based inhibitors to specific protein structures have been summarized and the clinical significance of targeting these proteins for cancer treatment and prevention has been discussed. The opening article by Sarkar and colleagues discusses the novel Notch signaling pathway proteins that play critical roles in maintaining the balance between cell proliferation, differentiation and apoptosis. The authors review the structures and functions of notch signaling proteins and describe how deregulation of this pathway is involved in tumor development and progression, leading to metastasis and the ultimate demise of patients diagnosed with cancer. The authors also summarize the role of several Notch inhibitors, especially“natural agents” that could represent novel therapeutic strategies in targeting Notch signaling toward better treatment outcome of cancer patients. The complexes called “mammalian target of rapamycin” (mTOR) have attracted great attention recently due to the involvement of mTOR complexes in the development of various diseases including cancer, diabetes and obesity. Zhou and Huang discuss the advances in studies of the mTOR complexes, including mTOR interacting proteins, upstream regulators and downstream effectors, as well as the possibility of targeting mTOR complexes for cancer treatment and prevention. PI3Ks are oncogenic that coordinate various fundamental cellular responses including mitogenic signaling, proliferation, and vesicular trafficking. Overexpression of PI3Ks caused by genetic alterations has been frequently observed in different human cancers, suggesting that PI3Ks are suitable targets for therapeutic intervention. The article by Wu looks at recent progress in the study of PI3Ks and discusses several unique PI3Ks' oncogenic properties as well as their prognostic and therapeutic implications. Other oncoproteins, such as EGFR, play a vital role in regulating proliferation, differentiation, migration, angiogenesis, and cell death processes. Majumdar and co-authors review the involvement of EGFR in regulating events of gastrointestinal (GI) cancers during advancing age. The authors discuss current available therapeutics, such as targeting these receptors by peptidebased inhibitors or targeting GI cancer stem cells. The androgen receptor (AR) is another “oncoprotein” highlighted in this issue. AR is critical for proliferation of human prostate cancer cells, as both a transcription factor and an interacting protein with components of the pre-replication complex and DNA replication machinery. Reddy and co-authors review the newly identified role of AR protein in prostate cancer cell cycle regulation and discuss its interaction with some cell cycle regulatory proteins and enzymes of DNA synthesis. The authors propose that these interactions may enable AR to exert control over the process of DNA synthesis, and alterations in these AR-binding proteins may lead to the development of hormone-refractory prostate cancer. An in-depth understanding of the structural interactions between AR and cell cycle regulators may facilitate the development of new strategies for the treatment of prostate cancer. Protease complexes are also potential targets for cancer therapy. The ubiquitin-proteasome system plays an essential regulatory role in several critical cellular processes. It has been reported that human cancer cells possess elevated level of proteasome activity and are more sensitive to proteasome inhibitors than normal cells, indicating that the inhibition of the ubiquitin-proteasome system could be used as a novel approach for cancer therapy. The paper by Chen and Dou summarizes the structure and catalytic activities of the proteasome complexes, the properties and mechanisms of action of various proteasome inhibitors, and the clinical development of proteasome inhibitors as novel anticancer agents. Instead of focusing “oncoproteins” as in the above six reviews, the last article by Stamenkovic and Yu describes a tumor suppressor protein called Merlin, a protein encoded by the neurofibromatosis type 2 (NF2) tumor suppressor gene. Merlin regulates the cell-cell and cell-matrix adhesions. It also regulates functions of the cell surface adhesion/extracellular matrix receptors and plays important roles in stabilizing the contact inhibition of proliferation and in regulating activities of several receptor tyrosine kinases. The authors suggest that Merlin is a negative regulator of growth and progression of several non-NF2 associated cancer types and this translational research has potential impact for the treatment of cancer patients with altered Merlin functions or pathways.