Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. High mortality from HCC is mainly due to widespread prevalence and the lack of effective treatment, since systemic chemotherapy is ineffective, while the targeted agent Sorafenib extends median survival only briefly. The steroidal saponin 20(S)-ginsenoside Rg3 from Panax ginseng C.A. Meyer is proposed to chemosensitize to various therapeutic drugs through an unknown mechanism. Since autophagy often serves as cell survival mechanism in cancer cells exposed to chemotherapeutic agents, we examined the ability of Rg3 to inhibit autophagy and chemosensitize HCC cell lines to doxorubicin in vitro. We show that Rg3 inhibits late stage autophagy, possibly through changes in gene expression. Doxorubicin-induced autophagy plays a protective role in HCC cells, and therefore Rg3 treatment synergizes with doxorubicin to kill HCC cell lines, but the combination is relatively nontoxic in normal liver cells. In addition, Rg3 was well-tolerated in mice and synergized with doxorubicin to inhibit tumor growth in HCC xenografts in vivo. Since novel in vivo inhibitors of autophagy are desirable for clinical use, we propose that Rg3 is such a compound, and that combination therapy with classical chemotherapeutic drugs may represent an effective therapeutic strategy for HCC treatment.

The current paradigm of noncanonical NF-κB signaling suggests that the loss of TRAF2, TRAF3 or cIAP1 and cIAP2 leads to stabilization of NF-κB-inducing kinase (NIK) to activate the noncanonical pathway. Although a crucial role of RIP1 in the TNFα-induced canonical NF-κB pathway has been well established, its involvement in noncanonical activation of NF-κB through the TNFR1 receptor, is unknown. Here we show that TNFα is capable of activating the noncanonical NF-κB pathway, but that activation of this pathway is negatively regulated by RIP1. In the absence of RIP1, TNFR1 stimulation leads to activation of the noncanonical NF-κB pathway through TRAF2 degradation, leading to NIK stabilization, IKKα phosphorylation and the processing of p100 to generate p52. Thus although RIP1−/− mouse embryonic fibroblasts are sensitive at early time points to cell death induced by TNFα, probably as a result of lack of canonical NF-κB activation, the late activation of the noncanonical NF-κB pathway protects the remaining cells from further cell death. The TNFR1-dependent noncanonical NF-κB activation in RIP1−/− cells suggests that there is functional interplay between the two NF-κB pathways during TNFR1 signaling, which might regulate the number and kinds of NF-κB transcription factors and thus finely control NF-κB-dependent gene transcription.

a b s t r a c tOne major obstacle in the clinical application of TRAIL as a cancer therapeutic agent is the acquisition of TRAIL resistance. We found that deficiency of TRADD sensitizes cells to TRAIL-induced apoptosis. Enhanced cell death in TRADD À/À MEFs is associated with defective NF-jB activation, indicating that the pro-survival function of TRADD in TRAIL signaling is mediated at least in part via NF-jB activation. Moreover, siRNA knock-down of TRADD in cancer cells sensitizes them to TRAIL-induced apoptosis. Thus, TRADD has a survival role in TRAIL signaling and may be one potential target for overcoming TRAIL resistance in cancer therapy. Structured summary of protein interactions:TRAIL physically interacts with FADD and RIP1 by pull down (View interaction)

Mutation breeding is useful for improving agronomic characteristics of various crops. In this study, we conducted a genetic diversity and association analysis of soybean mutants to assess elite mutant lines. On the basis of phenotypic traits, we chose 208 soybean mutants as a mutant diversity pool (MDP). We then investigated the genetic diversity and inter-relationships of these MDP lines using target region amplification polymorphism (TRAP) markers. Among the different TRAP primer combinations, polymorphism levels and polymorphism information content (PIC) values averaged 59.71% and 0.15, respectively. Dendrogram and population structure analyses divided the MDP lines into four major groups. According to an analysis of molecular variance (AMOVA), the percentage of inter-population variation among mutants was 11.320 (20.6%), whereas mutant intra-population variation ranged from 0.231 (0.4%) to 14.324 (26.1%). Overall, intra-population genetic similarity was higher than that of inter-populations. In an analysis of the association between TRAP markers and agronomic traits using three different statistical approaches based on the single factor analysis (SFA), the Q general linear model (GLM), and the mixed linear model (Q+K MLM), we detected six significant marker–trait associations involving five phenotypic traits. Our results suggest that the MDP has great potential for soybean genetic resources and that TRAP markers are useful for the selection of soybean mutants for soybean mutation breeding.

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