Fighting Carcinogenesis with Plant Metabolites by Weakening Proliferative Signaling and Disabling Replicative Immortality Networks of Rapidly Dividing and Invading Cancerous Cells.

BACKGROUND: Cancer, an uncontrolled multistage disease causing swift division of cells, is a leading disease with the highest mortality rate. Cellular heterogeneity, evading growth suppressors, resisting cell death, and replicative immortality drive the tumor progression by resisting the therapeutic action of existing anticancer drugs through a series of intrinsic and extrinsic cellular interactions. The innate cellular mechanisms also regulate the replication process as a fence against proliferative signaling, enabling replicative immortality through telomere dysfunction. AREA COVERED: The conventional genotoxic drugs have several off-target and collateral side effects associated with them. Thus, the need for the therapies targeting cyclin-dependent kinases or P13K signaling pathway to expose cancer cells to immune destruction, deactivation of invasion and metastasis, and maintaining cellular energetics is imperative. Compounds with anticancer attributes isolated from plants and rich in alkaloids, terpenes, and polyphenols have proven to be less toxic and highly targetspecific, making them biologically significant. This has opened a gateway for the exploration of more novel plant molecules by signifying their role as anticancer agents in synergy and alone, making them more effective than the existing cytotoxic regimens. EXPERT OPINION: In this context, the current review presented recent data on cancer cases around the globe, along with discussing the fundamentals of proliferative signaling and replicative immortality of cancer cells. Recent findings were also highlighted, including antiproliferative and antireplicative action of plant-derived compounds, besides explaining the need for improving drug delivery systems.

Potassium and Chloride Ion Channels in Cancer: A Novel Paradigm for Cancer Therapeutics.

Cancer is a collection of diseases caused by specific changes at the genomic level that support cell proliferation indefinitely. Traditionally, ion channels are known to control a variety of cellular processes including electrical signal generation and transmission, secretion, and contraction by controlling ionic gradients. However, recent studies had brought to light important facts on ion channels in cancer biology.In this review we discuss the mechanism linking potassium or chloride ion channel activity to biochemical pathways controlling proliferation in cancer cells and the potential advantages of targeting ion channels as an anticancer therapeutic option.

Protein arginine methyltransferase 5 (PRMT5) dysregulation in cancer.

Protein arginine methyltransferases (PRMTs) are known for their ability to catalyze methylation of specific arginine residues in a wide variety of cellular proteins, which are involved in a plethora of processes including signal transduction, transcription, and more recently DNA recombination. All members of the PRMT family can be grouped into three main classes depending on the type of methylation they catalyze. Type I PRMTs induce monomethylation and asymmetric dimethylation, while type II PRMTs catalyze monomethylation and symmetric dimethylation of specific arginine residues. In contrast, type III PRMTs carry out only monomethylation of arginine residues. In this review, we will focus on PRMT5, a type II PRMT essential for viability and normal development, which has been shown to be overexpressed in a wide variety of cancer cell types, owing it to the crucial role it plays in controlling key growth regulatory pathways. Furthermore, the role of PRMT5 in regulating expression and stability of key transcription factors that control normal stem cell function as well as cancer stem cell renewal will be discussed. We will review recent work that shows that through its ability to methylate various cellular proteins, PRMT5 functions as a master epigenetic regulator essential for growth and development, and we will highlight studies that have examined its dysregulation and the effects of its inhibition on cancer cell growth.

Endosomal H2O2 production leads to localized cysteine sulfenic acid formation on proteins during lysophosphatidic acid-mediated cell signaling.

Lysophosphatidic acid (LPA) is a growth factor for many cells including prostate and ovarian cancer-derived cell lines. LPA stimulates H2O2 production which is required for growth. However, there are significant gaps in our understanding of the spatial and temporal regulation of H2O2-dependent signaling and the way in which signals are transmitted following receptor activation. Herein, we describe the use of two reagents, DCP-Bio1 and DCP-Rho1, to evaluate the localization of active protein oxidation after LPA stimulation by detection of nascent protein sulfenic acids. We found that LPA stimulation causes internalization of LPA receptors into early endosomes that contain NADPH oxidase components and are sites of H2O2 generation. DCP-Rho1 allowed visualization of sulfenic acid formation, indicative of active protein oxidation, which was stimulated by LPA and decreased by an LPA receptor antagonist. Protein oxidation sites colocalized with LPAR1 and the endosomal marker EEA1. Concurrent with the generation of these redox signaling-active endosomes (redoxosomes) is the H2O2- and NADPH oxidase-dependent oxidation of Akt2 and PTP1B detected using DCP-Bio1. These new approaches therefore enable detection of active, H2O2-dependent protein oxidation linked to cell signaling processes. DCP-Rho1 may be a particularly useful protein oxidation imaging agent enabling spatial resolution due to the transient nature of the sulfenic acid intermediate it detects.