Current Cancer Drug Targets - Volume 19, Issue 6, 2019

Protein-Protein Interactions (PPIs) drive major signalling cascades and play critical role in cell proliferation, apoptosis, angiogenesis and trafficking. Deregulated PPIs are implicated in multiple malignancies and represent the critical targets for treating cancer. Herein, we discuss the key protein-protein interacting domains implicated in cancer notably PDZ, SH2, SH3, LIM, PTB, SAM and PH. These domains are present in numerous enzymes/kinases, growth factors, transcription factors, adaptor proteins, receptors and scaffolding proteins and thus represent essential sites for targeting cancer. This review explores the candidature of various proteins involved in cellular trafficking (small GTPases, molecular motors, matrix-degrading enzymes, integrin), transcription (p53, cMyc), signalling (membrane receptor proteins), angiogenesis (VEGFs) and apoptosis (BCL-2family), which could possibly serve as targets for developing effective anti-cancer regimen. Interactions between Ras/Raf; X-linked inhibitor of apoptosis protein (XIAP)/second mitochondria-derived activator of caspases (Smac/DIABLO); Frizzled (FRZ)/Dishevelled (DVL) protein; beta-catenin/T Cell Factor (TCF) have also been studied as prospective anticancer targets. Efficacy of diverse molecules/ drugs targeting such PPIs although evaluated in various animal models/cell lines, there is an essential need for human-based clinical trials. Therapeutic strategies like the use of biologicals, high throughput screening (HTS) and fragment-based technology could play an imperative role in designing cancer therapeutics. Moreover, bioinformatic/computational strategies based on genome sequence, protein sequence/structure and domain data could serve as competent tools for predicting PPIs. Exploring hot spots in proteomic networks represents another approach for developing targetspecific therapeutics. Overall, this review lays emphasis on a productive amalgamation of proteomics, genomics, biochemistry, and molecular dynamics for successful treatment of cancer.

Ovarian cancer is a leading cause of death worldwide from gynecological malignancies, mainly because there are few early symptoms and the disease is generally diagnosed at an advanced stage. In addition, despite the effectiveness of cytoreductive surgery for ovarian cancer and the high response rates to chemotherapy, survival has improved little over the last 20 years. The management of patients with ovarian cancer also remains similar despite studies showing striking differences and heterogeneity among different subtypes. It is therefore clear that novel targeted therapeutics are urgently needed to improve clinical outcomes for ovarian cancer. To that end, several membrane receptors associated with pivotal cellular processes and often aberrantly overexpressed in ovarian cancer cells have emerged as potential targets for receptor-mediated therapeutic strategies including specific agents and multifunctional delivery systems based on ligand-receptor binding. This review focuses on the profiles and potentials of such strategies proposed for ovarian cancer treatment and imaging.

The multifunctional signaling hub p62 is well recognized as a ubiquitin sensor and a selective autophagy receptor. As a ubiquitin sensor, p62 promotes NFΚB activation by facilitating TRAF6 ubiquitination and aggregation. As a selective autophagy receptor, p62 sorts ubiquitinated substrates including p62 itself for lysosome-mediated degradation. p62 plays crucial roles in myriad cellular processes including DNA damage response, aging/senescence, infection and immunity, chronic inflammation, and cancerogenesis, dependent on or independent of autophagy. Targeting p62-mediated autophagy may represent a promising strategy for clinical interventions of different cancers. In this review, we summarize the transcriptional and post-translational regulation of p62, and its mechanistic roles in cancers, with the emphasis on its roles in regulation of DNA damage response and its connection to the cGAS-STING-mediated antitumor immune response, which is promising for cancer vaccine design.

Background: c-Myc plays a major role in the maintenance of glycolytic metabolism and hematopoietic stem cell (HSC) quiescence. Objective: Targeting modulators of HSC quiescence and metabolism could lead to HSC cell cycle entry with concomitant expansion. Methods and Results: Here we show that c-Myc inhibitor 10074-G5 treatment leads to 2-fold increase in murine LSKCD34low HSC compartment post 7 days. In addition, c-Myc inhibition increases CD34+ and CD133+ human HSC number. c-Myc inhibition leads to downregulation of glycolytic and cyclindependent kinase inhibitor (CDKI) gene expression ex vivo and in vivo. In addition, c-Myc inhibition upregulates major HDR modulator Rad51 expression in hematopoietic cells. Besides, c-Myc inhibition does not alter proliferation kinetics of endothelial cells, fibroblasts or adipose-derived mesenchymal stem cells, however, it limits bone marrow derived mesenchymal stem cell proliferation. We further demonstrate that a cocktail of c-Myc inhibitor 10074-G5 along with tauroursodeoxycholic acid (TUDCA) and i-NOS inhibitor L-NIL provides a robust HSC maintenance and expansion ex vivo as evident by induction of all stem cell antigens analyzed. Intriguingly, the cocktail of c-Myc inhibitor 10074-G5, TUDCA and L-NIL improves HDR related gene expression. Conclusion: These findings provide tools to improve ex vivo HSC maintenance and expansion, autologous HSC transplantation and gene editing through modulation of HSC glycolytic and HDR pathways.

Background: The major attention has been received by the natural products in the prevention of diseases due to their pharmacological role. Objective: The major focus of the study was to search for highly potential anti-cancer compounds from marine Streptomyces sp. VITJS4 (NCIM No. 5574). Methods: Cytotoxic assay was examined by MTT assay on HepG2 cells. Bioassay-guided fractionation of the ethyl acetate extract from the fermented broth led to the isolation of the compound. The lead compound structure was elucidated by combined NMR and MS analysis, and the absolute configuration was assigned by extensive spectroscopic analysis. Results: On the basis of spectroscopic data, the compound was identified as 1, 2 benzenedicarboxylic acid, mono 2-ethylhexyl (BMEH). The compound exhibited in vitro anticancer potential against liver (HepG2) cancer cells. Based on the flow cytometric analysis, it was evident that the BMEH was also effective in arresting the cell cycle at G1 phase. Further, the Western blotting analysis confirmed the down-regulation of Bcl-2 family proteins, and activation of caspase-9 and 3. The molecular docking and dynamics simulation were performed to reveal the activity of the compound over a time period of 10ns. From the molecular dynamics studies, it was found that the stability and compactness were attained by the protein by means of the compound interaction. Conclusion: This study highlights our collaborative efforts to ascertain lead molecules from marine actinomycete. This is the first and foremost report to prove the mechanistic studies of the purified compound 1, 2-benzene dicarboxylic acid, mono(2-ethylhexyl) ester isolated from marine Streptomyces sp.VITJS4 against HepG2 cells.

Background: The oncoprotein binding (OPB) domain of Yin Yang 1 (YY1) consists of 26 amino acids between G201 and S226, and is involved in YY1 interaction with multiple oncogene products, including MDM2, AKT, EZH2 and E1A. Through the OPB domain, YY1 promotes the oncogenic or proliferative regulation of these oncoproteins in cancer cells. We previously demonstrated that a peptide with the OPB sequence blocked YY1-AKT interaction and inhibited breast cancer cell proliferation. Objective: In the current study, we characterized the OPB domain and determined a minimal region for peptide design to suppress cancer cells. Methods: Using alanine-scan method, we identified that the amino acids at OPB C-terminal are essential to YY1 binding to AKT. Further studies suggested that serine and threonine residues, but not lysines, in OPB play a key role in YY1-AKT interaction. We generated GFP fusion expression vectors to express OPB peptides with serially deleted N-terminal and found that OPB1 (i.e. G201-S226) is cytoplasmic, but OPB2 (i.e. E206-S226), OPB3 (i.e. E206-S226) and control peptide were both nuclear and cytoplasmic. Results: Both OPB1 and 2 inhibited breast cancer cell proliferation and migration, but OPB3 exhibited similar effects to control. OPB1 and 2 caused cell cycle arrest at G1 phase, increased p53 and p21 expression, and reduced AKT(S473) phosphorylation in MCF-7 cells, but not in MDA-MB-231 cells. Conclusion: Overall, the serines and threonines of OPB are essential to YY1 binding to oncoproteins, and OPB peptide can be minimized to E206-S226 that maintain inhibitory activity to YY1- promoted cell proliferation.