Gomisin A Enhances Tumor Necrosis Factor-α-Induced G1 Cell Cycle Arrest <i>via</i> Signal Transducer and Activator of Transcription 1-Mediated Phosphorylation of Retinoblastoma Protein

Abstract

Gomisin A, a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra chinensis, has been reported as an anti-cancer substance. In this study, we investigated the effects of gomisin A on cancer cell proliferation and cell cycle arrest in HeLa cells. Gomisin A significantly inhibited cell proliferation in a dose-dependent manner after 72 h treatment, especially in the presence of tumor necrosis factor-α (TNF-α), due to cell cycle arrest in the G1 phase with the downregulation of cyclin D1 expression and Retinoblastoma (RB) phosphorylation. In addition, gomisin A in combination with TNF-α strongly suppressed the expression of signal transducer and activator of transcription 1 (STAT1). Inhibition of STAT1 pathways by a small-interfering RNA against STAT1 and AG490 Janus kinase (JAK) kinase inhibitor AG490 reduced the cyclin D1 expression and RB phosphorylation, indicating that JAK-mediated STAT1 activation is involved in gomisin A-induced G1 cell cycle arrest.Key words gomisin A; tumor necrosis factor-α; cell cycle; cyclin D1; Retinoblastoma Cancer cells often have a selective growth advantage due to deregulation of cell cycle proteins, causing aberrant growth signaling that drives tumor development.1-4) The eukaryotic cell cycle is regulated through the sequential activation and inactivation of cyclin-dependent kinases (CDKs). Deregulation of G1 to S-phase transition is implicated in the pathogenesis of most human cancers. 5) Retinoblastoma protein (RB) is a critical target protein in G1-S checkpoint control. Phosphorylation of RB by CDK/cyclin complex results in the release of active E2F transcription factor to stimulate the transcription of genes involved in DNA synthesis and S-phase progression. 6,7)Cyclin D1 can accelerate the progress of cells through the G1 phase by binding to CDKs and subsequently phosphorylating RB. Overexpression of cyclin D1 has been shown to shorten the G1 phase in cancer cells and is most frequently associated with human cancer. 8,9) Cyclin D1 is rarely mutated, but its overexpression confers a selective growth advantage and hence acts as a driver of neoplastic growth in various cancers. 10,11)The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway plays a significant role in various physiological processes, including immune function, cell growth, differentiation, and hematopoiesis. 12) Constitutive activation of STAT3 correlates with cell proliferation in breast carcinoma 13) and non small-cell lung cancer.14) It has been revealed that inhibition of JAK-STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells.15) Activated STAT3 correlates with elevated cyclin D1 protein in primary breast tumors and breast cancer-derived cell lines.16) Our recent study demonstrated that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis was enhanced by STAT1 knockdown.17) Consequently, regulation of STATs can be considered as a key major target in controlling the gr...

Current knowledge of Schisandra chinensis (Turcz.) Baill. (Chinese magnolia vine) as a medicinal plant species: a review on the bioactive components, pharmacological properties, analytical and biotechnological studies

“…A recent investigation concerned the effects of gomisin A on cancer cell proliferation and cell cycle arrest in HeLa cells. Gomisin A significantly inhibited cell proliferation, especially in the presence of tumour necrosis factor-α (TNF-α) (Waiwut et al 2012). …”

Gomisin A Suppresses Colorectal Lung Metastasis by Inducing AMPK/p38-Mediated Apoptosis and Decreasing Metastatic Abilities of Colorectal Cancer Cells

“…G.A significantly downregulated the cyclin D1 and CDK4 expression levels in CT26 and HT29 cells ( Figures 3D,E ). According to previous study, G.A can induce cell cycle arrest of HeLa cells by regulating cyclin D1 expression via STAT1 signaling (Waiwut et al, 2012). Thus, mRNA expression levels of STAT1 in G.A-treated CT26 and HT29 cells were confirmed and high concentration of G.A significantly decreased STAT1 expression ( Supplementary Figure 1 ).…”

“…Furthermore, G.A enhances tumor necrosis factor (TNF)-α-induced G1 cell cycle arrest by downregulating cyclin D1 and retinoblastoma phosphorylation in the HeLa cervical cancer cell line (Waiwut et al, 2012). In this study, G.A reduced the viability of various CRC cell lines by inducing G0/G1 phase arrest and apoptosis.…”

Phytochemical studies and biological activity of three Chinese Schisandra species (Schisandra sphenanthera, Schisandra henryi and Schisandra rubriflora): current findings and future applications

“…As demonstrated by studies, dibenzocyclooctadiene lignans also have protective effects on the myocardium and properties stimulating the uterine muscle. Moreover, previous studies have confirmed their beneficial effects on the central nervous system by protecting nerve cells from dying and increasing the concentration of neurotransmitters (Hernandez et al 1988;Lu and Liu 1991;Yasukawa et al 1992;Hancke et al 1994;Ko et al 1995;World Health Organization 2007;Hwang et al 2009Hwang et al , 2011Miao et al 2009;Xiao et al 2010c;Chiu et al 2011;Waiwut et al 2012;Chen et al 2012;Casarin et al 2014;Hu et al 2014;Wang et al 2015;Thandavarayan et al 2015;Szopa et al 2016aSzopa et al , 2017a. Detailed directions of the biological activity of dibenzocyclooctadiene lignans are presented in Table 2.…”