Abstract. Cancer remains a leading cause of mortality worldwide, therefore food products are being investigated for potential prevention or treatment strategies. The ingredient, barley grass extract (Hordeum vulgare L.; Bex) is used to prevent or ameliorate various types of disease. In cancer, Bex has been revealed to inhibit tumor growth. However, its effect on cancer cells is yet to be clearly defined. In the present study, the effect of Bex on cancer cell growth was investigated. Bex inhibited the viabilities of breast and prostate cancer cells according to the results of MTT assays. Accordingly, Bex caused apoptosis, which was confirmed by Annexin V staining and western blot analysis for poly (ADP-ribose) polymerase and caspases. Furthermore, Bex increased the intracellular levels of reactive oxygen species (ROS), and N-acetyl-L-cystein blocked Bex-induced apoptosis. Therefore, the study demonstrated that Bex causes apoptosis of breast and prostate cancer cells by increasing intracellular ROS levels. IntroductionCancer is one of the leading causes of mortality worldwide (1,2). Despite numerous cancer studies and the development of various anti-cancer therapeutic agents, cancer remains dangerous. Anti-cancer therapeutic agents are chemically or biologically produced, and their effects are well defined (3-7). However, treatments continue to be associated with adverse effects and the majority of patients have an aversion to them (8).Herbal products have long been used to prevent or treat diseases, including cancer (9-12). Furthermore, certain anti-cancer therapeutic agents that are chemically produced originate from herbal products and their chemical characteristics are modified (7,(12)(13)(14). Typically, patients prefer to take herbal products (15-18); herbal products have historically been used as traditional medicines, such as traditional Chinese and Korean medicines, Kampo medicines and Ayurvedic medicine (13,14,19). Certain herbal products were demonstrated to treat cancer and/or reduce the side effects of cancer treatment (13,(15)(16)(17)(19)(20)(21). Therefore, herbal products are considered to be promising for cancer prevention and treatment.Barley grass extract (Hordeum vulgare L.; Bex) has long been used as a food product. Its biological effects have also been addressed by various in vitro and in vivo studies, although evidence there is limited evidence of the efficacy of Bex against specific conditions (22). The effect of Bex on the immune system was revealed in in vitro and in vivo experimental sets (23-25). Accordingly, Bex inhibited atopic dermatitis in NC/Nga mice by altering the expression levels of cytokines (26). Similarly, Bex repressed lipopolysaccharide-induced inflammation (27). Furthermore, its effect in type 2 diabetes was revealed in a genetically engineered mouse model and patients (28,29). Therefore, the effects of Bex on particular diseases have been demonstrated at least in experimental systems. A previous study revealed that Bex caused apoptosis of leukemia and lymphoma cell lines...

Progression of chronic myeloid leukemia, marked by the oncogenic Bcr-Abl mutation, is tightly associated with an alteration of the p53 pathway. It is known that butein extracted from various plants represses cancer growth. Although the anticancer effects of butein are widely accepted, the mechanisms by which butein induces apoptosis of chronic myeloid leukemia cells remains to be elucidated. The present study demonstrated that butein-induced apoptosis was mediated by p53. KBM5 chronic myeloid leukemia (CML) cells expressing wild-type p53 were more sensitive to butein compared with p53-null K562 CML cells in terms of apoptotic cell death. In addition, butein arrested KBM5 cells at S-phase and altered the expression levels of certain cyclins and the p53-downstream targets, MDM2 and p21. In addition, while butein reduced the protein expression of MDM2 in the KBM5 and K562 cells, it resulted in proteasome-independent MDM2 degradation in p53-expressing KBM5 cells, however, not in p53-null K562 cells. Therefore, the present study suggested that p53 causes the butein-mediated apoptosis of leukemic cells. Citation Format: SeoYeon Lee, Yu-Jeong Choi, Myeong-sun Kim, Sooyeon Kang, Ji Hye Kim, Sang Mi Woo, Seong-Gyu Ko, Sukjoong Oh. p53 causes butein-mediated apoptosis of chronic myeloid leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 711.

Defining the full complement of substrates for each ubiquitin ligase remains an important challenge. Improvements in mass spectrometry instrumentation and computation and in protein biochemistry methods have resulted in several new methods for ubiquitin ligase substrate identification. Here we used the parallel adapter capture (PAC) proteomics approach to study βTrCP2, a substrate adaptor for the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complex. The processivity of the ubiquitylation reaction necessitates transient physical interactions between βTrCP2 and its substrates, thus making biochemical purification of FBXW11-bound substrates difficult. Using the PAC-based approach, we inhibited the proteasome to “trap” ubiquitylated substrates on the SCF (βTrCP2) E3 complex. Comparative mass spectrometry analysis of immunopurified βTrCP2 protein complexes before and after proteasome inhibition revealed 21 known and 23 putatively novel substrates. Interestingly, many novel substrates for βTrCP2, including TBC1D4, HCFC1, DENND4C, FNIP1, and FLCN are related to cell metabolism. TBC1D4 encodes a GTPase activating protein for the small GTPase Rab that controls insulin-dependent trafficking of the GLUT4 glucose transporter in adipocytes. DENND4C acts as a guanine nucleotide exchange factor for Rab10 and its activity is required for insulin-stimulated GLUT4 translocation to plasma membrane in adipocytes. HCFC1 is a member of the host cell factor family, affecting gluconeogenesis by modulating PGC-1α stability. These suggest βTrCP2 might play important roles in glucose homeostasis by regulating stability of several different target proteins. Here, in focused study, we found that βTrCP1/2 bound, polyubiquitylated, and destabilized FNIP1, FLCN interacting protein 1. We further demonstrated that FNIP1 degradation was promoted by AMPK activation after glucose depletion and expression of a degradation-resistant FNIP1 mutant results in sustained activation of mTORC1 signaling. Hence, our findings reveal that βTrCP1/2 is involved in nutrient sensing through the AMPK-FLCN-FNIP1 and mTORC1 signaling pathways. Citation Format: Tai Young Kim, Jee Yun Chang, Jin Mo Ku, Se Hyang Hong, ji Hye Kim, Hyeong Sim Choi, Kangwook Lee, Myeong-Sun Kim, Sang Mi Woo, Michael B. Major, Seong-Gyu Ko. Substrate trapping proteomics reveals novel mechanism for regulation of mTORC1 signaling by βTrCP-FNIP1/2-FLCN axis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4543.

Pancreatic cancer has a poor prognosis and very low survival rate over the world. Because pancreatic cancer probably is diagnosed at a late stage, aggressive local invasion, and poor response to chemotherapy. Gemcitabine was the standard treatment for advanced and metastatic pancreatic cancer patients, but it is associated with multiple adverse effects-fever, fatigue, nausea, and drug resistance. Whether cucurbitacin D has any efficacy against human pancreatic cancer was examined in cell culture system. In vitro, cell viability was measured by MTT assay to recognize of cell cytotoxicity. Consequently, cytotoxicity was observed at a low concentration of cucurbitacin D. Wound healing assay and clonogenic assay indicated that cucurubitacin D inhibited the growth of cell growth through cyclins and CDKs regulation, and decreased colony-forming ability. Also, this compound down-regulated expression level of anti-apoptotic protein, Bcl-2, up-regulated of pro-apoptotic molecule Bax, and activated caspase-8, caspase-3 cascade extrinsic pathway. Additionally, PARP, caspase-3 substrate, protein was cleaved by cucurbitacin D treatment. Overall, our study suggest that cucurbitacin D could be a clinical medicine for the treatment of pancreatic cancers. Citation Format: Myeong-Sun Kim, Ji Hye Kim, Jin Mo Ku, Se Hyang Hong, Kangwook Lee, Hyeong Sim Choi, Sang Mi Woo, Jee Yun Chang, Tai Young Kim, Seong Gyu Ko Ko. Cyclins and CDKs regulation and caspase cascade activation by cucurbitacin D induced cell cycle arrest and apoptosis in pancreatic tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3522.

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