Side effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. In this report we determined whether and how cerium oxide nanoparticles (CONPs) sensitize pancreatic cancer cells to RT. CONP pretreatment enhanced radiation-induced reactive oxygen species (ROS) production preferentially in acidic cell-free solutions as well as acidic human pancreatic cancer cells. In acidic environments, CONPs favor the scavenging of superoxide radical over the hydroxyl peroxide resulting in accumulation of the latter whereas in neutral pH CONPs scavenge both. CONP treatment prior to RT markedly potentiated the cancer cell apoptosis both in culture and in tumors and the inhibition of the pancreatic tumor growth without harming the normal tissues or host mice. Mechanistically, CONPs were not able to significantly impact RT-induced DNA damage in cancer cells, thereby ruling out sensitization through increased mitotic catastrophe. However, JNK activation, which is known to be a key driver of RT-induced apoptosis, was significantly upregulated by co-treatment with CONPs and RT in pancreatic cancer cells in vitro and human pancreatic tumors in nude mice in vivo compared to CONPs or RT treatment alone. Further, CONP-driven increase in RT-induced JNK activation was associated with marked increases in Caspase 3/7 activation, indicative of apoptosis. We have shown CONPs increase ROS production in cancer cells; ROS has been shown to drive the oxidation of thioredoxin (TRX) 1 which results in the activation of Apoptosis Signaling iv Kinase (ASK) 1. The dramatic increase in ASK1 activation following the co-treatment of pancreatic cancer cells with CONPs followed by RT in vitro suggests that increased the c-Jun terminal kinase (JNK) activation is the result of increased TRX1 oxidation. The ability of CONPs to sensitize pancreatic cancer cells to RT was mitigated when the TRX1 oxidation was prevented by mutagenesis of a cysteine residue, or the JNK activation was blocked by an inhibitor,. Additionally, angiogenesis in pancreatic tumors treated with CONPs and RT was significantly reduced compared to other treatment options. Taken together, these data demonstrate an important role and mechanisms for CONPs in specifically killing cancer cells and provide novel insight into the utilization of CONPs as a radiosensitizer and therapeutic agent for pancreatic cancer.

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学位プログラム名: 京都大学大学院思修館 / 京都大学 / 0048 / 新制・課程博士 / 博士(総合学術) / 甲第21931号 / 総総博第6号 / 新制||総総||1(附属図書館) / 京都大学大学院総合生存学館総合生存学専攻 / (主査)教授 阪井 康能, 教授 山口 栄一, 教授 積山 薫 / 学位規則第4条第1項該当 / Doctor of Philosophy / Kyoto University / DGAM

Abiotic stresses like salinity, drought, and extreme temperature are constantly on the rise, posing a very high risk to global agricultural productivity and food security. Hence, understanding stress signaling pathways can help engineer plants that can better withstand stress in unfavorable conditions. The salicylic acid (SA) signaling pathway has been widely studied for its important role in mediating abiotic stress in plants. In tobacco plants, Salicylic Acid Binding Protein 2 (SABP2), a methyl esterase enzyme, catalyzes the conversion of methyl salicylate (MeSA) to SA, which triggers the defense response via the SA-mediated signaling pathway. SIP-428 (SABP2 Interacting Protein-428) is an NAD+ dependent SIR2-like (Silent Information Regulator) deacetylase enzyme that likely interacts with SABP2 during SA biosynthesis. In previous studies, SIP-428 has been shown to be a negative regulator of plant growth under abiotic stress (NaCl and mannitol in vivo). Reactive Oxygen Species (ROS) are oxidizing oxygen products that accumulate under stress conditions, and at high levels can be very harmful to plants. Antioxidant enzymes such as catalase (CAT), guaiacol peroxidase (POD), ascorbate peroxidase (APX), and superoxide dismutase (SOD) are actively involved in lowering the ROS levels in the cell by combating the oxidative stress. The objective of this study was to analyze the regulatory functions of SIP-428 in ROS signaling of tobacco plants through the biochemical quantification of POD and CAT activities. We investigated the SIP-428 RNAi-silenced tobacco plants for the POD and CAT enzyme activities in Osmotic (Mannitol) and Salinity (NaCl) stressed plants. Our results showed that SIP-428 plays a significant role in modulating antioxidant enzymes in stressed plants. This study has improved our understanding of some regulatory roles of SIP428, and its application can be used to enhance stress tolerance via the use of synthetic biology.

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