Cytochrome P450 1A2 overcomes nuclear factor kappa B-mediated sorafenib resistance in hepatocellular carcinoma.

Sorafenib resistance has become the main obstacle in the effective treatment of advanced hepatocellular carcinoma (HCC) patients. Activation of nuclear factor kappa B (NF-κB) is a newly identified mechanism that contributes to desensitized sorafenib. Cytochrome P450 1A2 (CYP1A2) functions as a tumor suppressor in HCC and its expression is negatively associated with NF-κB in the liver. This study aimed to study whether CYP1A2 could overcome sorafenib resistance. To investigate whether CYP1A2 and NF-κB p65 played roles in sorafenib desensitization, we established sorafenib-resistant (SR) HCC cells. SR cells decreased the expression of CYP1A2 along with the upregulation of NF-κB p65. CYP1A2 overexpression attenuated SR cell proliferation, increased sorafenib sensitivity, and inhibited the NF-κB pathway, whereas CYP1A2 silence showed opposite effects. Sorafenib, in combination with omeprazole, a CYP1A2 inducer, significantly hindered the growth and invasion of SR cells in vitro as well as decreased the tumor growth in vivo. The combination treatment markedly increased CYP1A2 expression and inhibited the sorafenib-induced NF-κB signaling. In addition, the overexpression of NF-κB p65 stimulated the SR cell growth and desensitized sorafenib in SR cells, where CYP1A2 overexpression reversed the phenomenon. Lastly, the majority of HCC tissue samples displayed decreased CYP1A2 but increased NF-κB p65 protein expression. Collectively, CYP1A2 can sensitize SR cells to sorafenib via inhibiting NF-κB p65 axis. Omeprazole in combination with sorafenib exerts a synergistic effect in alleviating acquired sorafenib resistance.

ZBP-89 negatively regulates self-renewal of liver cancer stem cells via suppression of Notch1 signaling pathway.

Liver cancer stem cells (LCSCs) initiate hepatocellular carcinoma (HCC) and contribute to its recurrence and treatment resistance. Studies have suggested ZBP-89 as a candidate tumor suppressor in HCC. We explored the role of ZBP-89 in the regulation of LCSCs. This study was performed in liver tissue samples from 104 HCC patients, 2 cell lines and mouse tumor models. We demonstrated that ZBP-89 was weakly expressed in LCSCs. Patients with high expression of LCSC markers displayed reduced survivals and higher recurrence rates after curative surgical operation. The expression of ZBP-89 was predictive for decreased recurrence. LCSC markers were negatively correlated with ZBP-89 in HCC tissues and in enriched liver tumor spheres. The exogenous expression of ZBP-89 attenuated the tumor-sphere formation and secondary colony formation capabilities of LCSCs in vitro and tumorigenicity in vivo. Furthermore, the negative effect of ZBP-89 on cancer stemness was Notch1-dependent. Localized with Notch1 intracellular domain (NICD1) in the nucleus, ZBP-89 repressed the Notch1 signaling pathway by competitive binding to NICD1 with MAML1. Collectively, ZBP-89 negatively regulates HCC stemness via inhibiting the Notch1 signaling.

Cancer stem cells in hepatocellular carcinoma: an overview and promising therapeutic strategies.

The poor clinical outcome of hepatocellular carcinoma (HCC) patients is ascribed to the resistance of HCC cells to traditional treatments and tumor recurrence after curative therapies. Cancer stem cells (CSCs) have been identified as a small subset of cancer cells which have high capacity for self-renewal, differentiation and tumorigenesis. Recent advances in the field of liver CSCs (LCSCs) have enabled the identification of CSC surface markers and the isolation of CSC subpopulations from HCC cells. Given their central role in cancer initiation, metastasis, recurrence and therapeutic resistance, LCSCs constitute a therapeutic opportunity to achieve cure and prevent relapse of HCC. Thus, it is necessary to develop therapeutic strategies to selectively and efficiently target LCSCs. Small molecular inhibitors targeting the core stemness signaling pathways have been actively pursued and evaluated in preclinical and clinical studies. Other alternative therapeutic strategies include targeting LCSC surface markers, interrupting the CSC microenvironment, and altering the epigenetic state. In this review, we summarize the properties of CSCs in HCC and discuss novel therapeutic strategies that can be used to target LCSCs.

Targeting ZBP-89 for the treatment of hepatocellular carcinoma.

INTRODUCTION: Zinc-binding protein-89 (ZBP-89) is a Krüppel-type zinc-finger transcription factor that regulates target gene expression profiles via directly binding to GC-rich gene promoters, recruiting chromatin modifiers or by interacting with other proteins. The importance of ZBP-89 in the regulation of cell cycle arrest and apoptosis has led to increased interest and investigations for its role in cancer development. Areas covered: We describe ZBP-89 as a candidate therapeutic target for hepatocellular carcinoma (HCC) from several perspectives. ZBP-89 can upregulate apoptosis in HCC in a p53-dependent or - independent manner. In addition, the negative regulation of ZBP-89 on liver cancer stemness sheds light on its possible effect on sensitizing HCC to chemotherapies and the reduction of HCC relapse. The prognostic significance of ZBP-89 in HCC patients further suggests its clinical importance as a potential tumor suppressor. Expert opinion: Given the roles of ZBP-89 in HCC, we believe, ZBP-89 is a promising therapeutic target for enhancing apoptosis and diminishing the liver cancer stemness. At the same time, we also face a series of challenges, especially in the clinical implication of ZBP-89. Resolving the current controversies will advance the development of ZBP-89 for anti-HCC therapy.

p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis.

Macroautophagy mediates the selective degradation of proteins and non-proteinaceous cellular constituents. Here, we show that the N-end rule pathway modulates macroautophagy. In this mechanism, the autophagic adapter p62/SQSTM1/Sequestosome-1 is an N-recognin that binds type-1 and type-2 N-terminal degrons (N-degrons), including arginine (Nt-Arg). Both types of N-degrons bind its ZZ domain. By employing three-dimensional modeling, we developed synthetic ligands to p62 ZZ domain. The binding of Nt-Arg and synthetic ligands to ZZ domain facilitates disulfide bond-linked aggregation of p62 and p62 interaction with LC3, leading to the delivery of p62 and its cargoes to the autophagosome. Upon binding to its ligand, p62 acts as a modulator of macroautophagy, inducing autophagosome biogenesis. Through these dual functions, cells can activate p62 and induce selective autophagy upon the accumulation of autophagic cargoes. We also propose that p62 mediates the crosstalk between the ubiquitin-proteasome system and autophagy through its binding Nt-Arg and other N-degrons.Soluble misfolded proteins that fail to be degraded by the ubiquitin proteasome system (UPS) are redirected to autophagy via specific adaptors, such as p62. Here the authors show that p62 recognises N-degrons in these proteins, acting as a N-recognin from the proteolytic N-end rule pathway, and targets these cargos to autophagosomal degradation.

Recent advances in antimultiple myeloma drug development.

Multiple myeloma (MM) is the second most common hematological malignancy and is characterized by the aberrant proliferation of terminally differentiated plasma B cells with impairment in apoptosis capacity. Particularly, osteolytic bone diseases and renal failure resulting from hyperparaproteinemia and hypercalcemia have been the major serious sequelae that are inextricably linked with MM tumor progression. Despite the introduction of new treatment regimens, problematic neuropathy, thrombocytopenia, drug resistance and high MM relapse rates continue to plague the current therapies. New chemical agents are in development on the basis of understanding several signaling pathways and molecular mechanisms like tumor necrosis factor-α, proteasome, PI3K and MARKs. This review focuses on the most recent patents and clinical trials in the development of new medicine for the treatment of multiple myeloma. Furthermore, the important signaling pathways involved in the proliferation, survival and apoptosis of myeloma cells will be discussed.

Inhibition of NADPH oxidase 4-related signaling by sodium hydrosulfide attenuates myocardial fibrotic response.

BACKGROUND: Myocardial fibrosis plays a pivotal role in the development of heart failure. Hydrogen sulfide (H2S) is an endogenous gasotransmitter with potent cardioprotective properties; however, whether H2S is involved in fibrotic process remains unknown. This study aimed to explore the role of H2S in the process of cardiac fibrosis and the underlying mechanisms. METHODS: Myocardial infarction (MI) was established in rats by ligation of coronary artery. Activation of rat neonatal cardiac fibroblasts was induced by angiotensin II (Ang II). Fibrotic responses in ischemic myocardium and in Ang II-stimulated cardiac fibroblasts were examined. The effects of sodium hydrosulfide (NaHS, an exogenous H2S donor) on NADPH oxidase 4 (Nox4), reactive oxygen species (ROS) production, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, heme oxygenase-1 (HO-1), and cystathionine γ-lyase (CSE) were tested to elucidate the protective mechanisms of H2S on fibrotic response. RESULTS: NaHS treatment inhibited Ang II-induced expression of α-smooth muscle actin, connective tissue growth factor (CTGF), and type I collagen and upregulated expression of HO-1 in cardiac fibroblasts. Ang II-induced Nox4 expression in cardiac fibroblasts was quenched by NaHS and this was associated with a decreased ROS production and reduced ERK1/2 phosphorylation and CTGF expression. In vivo studies using MI model indicated that NaHS administration attenuated Nox4 expression and fibrotic response. Moreover, NaHS therapy also prevented cardiac inflammatory response accompanied by increases in HO-1 and CSE expression. CONCLUSIONS: The beneficial effect of H2S, at least in part, was associated with a decrease of Nox4-ROS-ERK1/2 signaling axis and an increase in HO-1 expression.