Aberrant gene silencing is highly associated with altered cell cycle regulation during carcinogenesis. In particular, silencing of the CDKN2A tumor suppressor gene, which encodes the p16INK4a protein, has a causal link with several different types of cancers. The p16INK4a protein plays an executional role in cell cycle and senescence through the regulation of the cyclin-dependent kinase (CDK) 4/6 and cyclin D complexes. Several genetic and epigenetic aberrations of CDKN2A lead to enhanced tumorigenesis and metastasis with recurrence of cancer and poor prognosis. In these cases, the restoration of genetic and epigenetic reactivation of CDKN2A is a practical approach for the prevention and therapy of cancer. This review highlights the genetic status of CDKN2A as a prognostic and predictive biomarker in various cancers.

Many beneficial properties have been attributed to (À)Àepi-gallocatechin gallate (EGCG), including chemopreventive, anticarcinogenic, and antioxidant actions. In this study, we investigated the effects of EGCG on the function of glucoseregulated protein 78 (GRP78), which is associated with the multidrug resistance phenotype of many types of cancer cells. Our investigation was directed at elucidating the mechanism of the EGCG and GRP78 interaction and providing evidence about whether EGCG modulates the activity of anticancer drugs through the inhibition of GRP78 function. We found that EGCG directly interacted with GRP78 at the ATP-binding site of protein and regulated its function by competing with ATP binding, resulting in the inhibition of ATPase activity. EGCG binding caused the conversion of GRP78 from its active monomer to the inactive dimer and oligomer forms. Further, we showed that EGCG interfered with the formation of the antiapoptotic GRP78-caspase-7 complex, which resulted in an increased etoposide-induced apoptosis in cancer cells. We also showed that EGCG significantly suppressed the transformed phenotype of breast cancer cells treated with etoposide. Overall, these results strongly suggested that EGCG could prevent the antiapoptotic effect of GRP78, which usually suppresses the caspase-mediated cell death pathways in drugtreated cancer cells, contributing to the development of drug resistance. (Cancer Res 2006; 66(18): 9260-9)

Extracellular and intracellular oxidants or electrophiles are key contributors to the damages in cellular macromolecules, such as DNA, proteins and lipids. Nrf2 is a master transcription factor that modulates a cellular antioxidant response program and plays an important role in the protection against oxidants and electrophiles. Keap1 is a regulator of Nrf2 by serving as a substrate adaptor for Cullin3-dependent E3 ubiquitin ligase. While Nrf2 activation is a feasible strategy for treatment of age-related diseases, aberrant Nrf2 activation also confers a selective growth advantage of tumor cells during chemotherapy or radiotherapy. In the present review, we provide an overview of the Keap1-Nrf2-ARE system, the domain organization of Nrf2 and Keap1, and the regulatory mechanisms of Nrf2 proteolysis by Keap1. We also discuss how Nrf2 prevents tumor promotion, hampers the sensitivity of selected tumors against chemotherapy or radiotherapy, and reprograms the metabolism to facilitate the tumor proliferation. Finally, we illustrate the current status in the development of Nrf2 chemical activators and inhibitors for the use of potential chemopreventive agents and chemotherapeutic adjuvants, respectively.

Cancer, being the second leading cause of mortality, exists as a formidable health challenge. In spite of our enormous efforts, the emerging complexities in the molecular nature of disease progression limit the real success in finding an effective cancer cure. It is now conceivable that cancer is, in fact, a progressive illness, and the morbidity and mortality from cancer can be reduced by interfering with various oncogenic signaling pathways. A wide variety of structurally diverse classes of bioactive phytochemicals have been shown to exert anticancer effects in a large number of preclinical studies. Multiple lines of evidence suggest that withaferin-A can prevent the development of cancers of various histotypes. Accumulating data from different rodent models and cell culture experiments have revealed that withaferin-A suppresses experimentally induced carcinogenesis, largely by virtue of its potent anti-oxidative, anti-inflammatory, anti-proliferative and apoptosis-inducing properties. Moreover, withaferin-A sensitizes resistant cancer cells to existing chemotherapeutic agents. The purpose of this review is to highlight the mechanistic aspects underlying anticancer effects of withaferin-A.

Persistent hair loss is a major cause of psychological distress and compromised quality of life in millions of people worldwide. Remarkable progress has been made in understanding the molecular basis of hair loss and identifying valid intracellular targets for designing effective therapies for hair loss treatment. Whereas a variety of growth factors and signaling pathways have been implicated in hair cycling process, the activation of Wnt/β-catenin signaling plays a central role in hair follicle regeneration. Several plant-derived chemicals have been reported to promote hair growth by activating Wnt/β-catenin signaling in various in vitro and in vivo studies. This mini-review sheds light on the role of Wnt/β-catenin in promoting hair growth and the current progress in designing hair loss therapies by targeting this signaling pathway.

Very little is known about the role of histone H3 phosphorylation in malignant transformation and cancer development. Here, we examine the function of H3 phosphorylation in cell transformation in vivo. Introduction of small interfering RNA-H3 into JB6 cells resulted in decreased epidermal growth factor (EGF)-induced cell transformation. In contrast, wildtype histone H3 (H3 WT)-overexpressing cells markedly stimulated EGF-induced cell transformation, whereas the H3 mutant S10A cells suppressed transformation. When H3 WT was overexpressed, EGF induction of c-fos and c-jun promoter activity was significantly increased compared with control cells but not in the H3 mutant S10A or S28A cells. In addition, activator protein-1 activity in H3 WT-overexpressing cells was markedly up-regulated by EGF in contrast to the H3 mutant S10A or S28A cells. These results indicate that the phosphorylation of histone H3 at Ser 10 is an essential regulatory mechanism for EGF-induced neoplastic cell transformation. (Cancer Res 2005; 65(13): 5818-27)

Epigallocatechin gallate (EGCG) is the major active polyphenol in green tea. Protein interaction with EGCG is a critical step in the effects of EGCG on the regulation of various key proteins involved in signal transduction. We have identified a novel molecular target of EGCG using affinity chromatography, two-dimensional electrophoresis, and mass spectrometry for protein identification. Spots of interest were identified as the intermediate filament, vimentin. The identification was confirmed by Western blot analysis using an anti-vimentin antibody. Experiments using a pull-down assay with A number of epidemiological studies have shown that the consumption of green tea may protect against many cancer types, including lung, prostate, and breast (1, 2). The inhibition of tumorigenesis by green or black tea preparations was demonstrated in animal models at various organ sites (3-5). The structures of the four major catechins, (Ϫ)-epigallocatechin gallate (EGCG), 1 (Ϫ)-epigallocatechin (EGC), (Ϫ)-epicatechin gallate (ECG), and (Ϫ)-epicatechin (EC), are shown in Fig. 1. EGCG is the major polyphenol in green tea and may account for 50 -80% of the total catechins in tea (4, 6, 7). The inhibitory activity of EGCG against tumorigenesis has been demonstrated. The mechanisms responsible for these cancer-preventive effects of tea are not very well understood but are being intensively investigated.Searching for the EGCG "receptor" or high affinity proteins that bind to EGCG is the first step to understanding the molecular and biochemical mechanisms of the anticancer effects of tea polyphenols. A few proteins that can directly bind with EGCG have been identified, including plasma proteins: fibronectin, fibrinogen, and histidine-rich glycoprotein (8); also fatty acid synthase (Fas) (9), laminin, and the 67-kDa laminin receptor (10, 11). Plasma proteins may act as carrier proteins for EGCG. Fas might trigger the cascade of Fas-mediated apoptosis, and the fact that EGCG can bind and regulate biological functions of the 67 laminin receptor has possible implications for prion-related diseases. However, the biologic and physiologic significance for the anticancer effects of tea polyphenols is not clear. Identification of new proteins binding with EGCG should help in the design of new strategies to prevent cancer.Mass spectrometry-based proteomic analysis is a powerful tool to identify proteins binding with EGCG. We used the JB6 mouse epidermal cell line, a system that has been used extensively as an in vitro model for tumor promotion studies (12), to identify novel proteins that bind with EGCG. The results indicated that EGCG binds with the intermediate filament (IF) protein, vimentin with high affinity (K d ϭ 3.3 nM). Vimentin, one of the type III IF proteins, is a major component of IFs and is expressed during development in a wide range of cells, including mesenchymal cells and in a variety of cultured cell lines and tumors (13,14). IFs are essential for structure and mechanical integration of the cellular space and a variety o...

The functional aspect of scalp hair is not only to protect from solar radiation and heat/cold exposure but also to contribute to one’s appearance and personality. Progressive hair loss has a cosmetic and social impact. Hair undergoes three stages of hair cycle: the anagen, catagen, and telogen phases. Through cyclical loss and new-hair growth, the number of hairs remains relatively constant. A variety of factors, such as hormones, nutritional status, and exposure to radiations, environmental toxicants, and medications, may affect hair growth. Androgens are the most important of these factors that cause androgenic alopecia. Other forms of hair loss include immunogenic hair loss, that is, alopecia areata. Although a number of therapies, such as finasteride and minoxidil, are approved medications, and a few others (e.g., tofacitinib) are in progress, a wide variety of structurally diverse classes of phytochemicals, including those present in ginseng, have demonstrated hair growth-promoting effects in a large number of preclinical studies. The purpose of this review is to focus on the potential of ginseng and its metabolites on the prevention of hair loss and its underlying mechanisms.