University of the Ryukyus · Faculty of Medicine

Research keywordscancer cell apoptosis・natural product anticancer agents・colon cancer・lung cancer drug resistance・immune checkpoint therapy・CTL peptide immunotherapy・TRAIL sensitivity

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• Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer.2018 · Pemetrexed (PEM) improves the overall survival of patients with advanced nonsmall cell lung cancer (NSCLC) when administered as maintenance therapy. However, PEM resistance often appears during the therapy. Although thymidylate synthase is known to be responsible for PEM resistance, no other mechanisms have been investigated in detail. In this study, we explored new drug resistance mechanisms of PEM-treated NSCLC using two combinations of parental and PEM-resistant NSCLC cell lines from PC-9 and A549. PEM increased the apoptosis cells in parental PC-9 and the senescent cells in parental A549. However, such changes were not observed in the respective PEM-resistant cell lines. Quantitative RT-PCR analysis revealed that, besides an increased gene expression of thymidylate synthase in PEM-resistant PC-9 cells, the solute carrier family 19 member1 (SLC19A1) gene expression was markedly decreased in PEM-resistant A549 cells. The siRNA-mediated knockdown of SLC19A1 endowed the parental cell lines with PEM resistance. Conversely, PEM-resistant PC-9 cells carrying an epidermal growth factor receptor (EGFR) mutation acquired resistance to a tyrosine kinase inhibitor erlotinib. Although erlotinib can inhibit the phosphorylation of EGFR and Erk, it is unable to suppress the phosphorylation of Akt in PEM-resistant PC-9 cells. Additionally, PEM-resistant PC-9 cells were less sensitive to the PI3K inhibitor LY294002 than parental PC-9 cells. These results indicate that SLC19A1 negatively regulates PEM resistance in NSCLC, and that EGFR-tyrosinekinase- inhibitor resistance was acquired with PEM resistance through Akt activation in NSCLC harboring EGFR mutations.
• HIF-1 alpha-derived peptide capable of inducing cancer-reactive cytotoxic T lymphocytes from HLA-A24+patients with RCC2018 · Minami Takafumi, Sugimoto Koichi, Shimizu Nobutaka, De Velasco Marco, Nozawa Masahiro, Yoshimura Kazuhiro, Harashima Nanae, Harada Mamoru, Uemura Hirotsugu
• HIF-2α dictates the susceptibility of pancreatic cancer cells to TRAIL by regulating survivin expression.2017 · Cancer cells develop resistance to therapy by adapting to hypoxic microenvironments, and hypoxia-inducible factors (HIFs) play crucial roles in this process. We investigated the roles of HIF-1 alpha and HIF-2 alpha in cancer cell death induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) using human pancreatic cancer cell lines. siRNA-mediated knockdown of HIF-2 alpha, but not HIF-1 alpha, increased susceptibility of two pancreatic cancer cell lines, Panc-1 and AsPC-1, to TRAIL in vitro under normoxic and hypoxic conditions. The enhanced sensitivity to TRAIL was also observed in vivo. This in vitro increased TRAIL sensitivity was observed in other three pancreatic cancer cell lines. An array assay of apoptosis-related proteins showed that knockdown of HIF-2 alpha decreased survivin expression. Additionally, survivin promoter activity was decreased in HIF-2 alpha knockdown Panc-1 cells and HIF-2 alpha bound to the hypoxia-responsive element in the survivin promoter region. Conversely, forced expression of the survivin gene in HIF-2 alpha shRNA-expressing Panc-1 cells increased resistance to TRAIL. In a xenograft mouse model, the survivin suppressant YM155 sensitized Panc-1 cells to TRAIL. Collectively, our results indicate that HIF-2 alpha dictates the susceptibility of human pancreatic cancer cell lines, Panc-1 and AsPC-1, to TRAIL by regulating survivin expression transcriptionally, and that survivin could be a promising target to augment the therapeutic efficacy of death receptor-targeting anti-cancer therapy.
• Contrasting effects of cyclophosphamide on anti-CTL-associated protein 4 blockade therapy in two mouse tumor models2017 · Immune checkpoint blockade is a promising anticancer therapy, but must be used in combination with other anticancer therapies to increase its therapeutic efficacy. Cyclophosphamide (CP) is a chemotherapeutic drug that shows immune-modulating effects. In this study, we examined the effect of CP on anti-CTL-associated protein 4 (CTLA-4) blockade therapy in two mouse tumor models. Drastic tumor regression was observed in the CT26 colon carcinoma model after i.p. injection of CP (100 mg/kg) followed by anti-CTLA-4 antibody. However, administration in the reverse order increased apoptosis in tumor-specific CD8(+) T cells. In the RENCA renal carcinoma model, the antitumor effect of combination therapy was marginal and the tumor-bearing state reduced body weight with an increased serum level of interleukin-6. Interestingly, although CP monotherapy increased myeloid-derived suppressor cells (MDSCs) in the spleens of both models, subsequent anti-CTLA-4 therapy increased MDSCs only in RENCA-bearing mice. Additionally, the serum levels of chemokine ligand 2 and C-X-C motif chemokine 10 were increased by the combination therapy only in RENCA-bearing mice and in vivo depletion of Gr-1(+) cells augmented the antitumor effect to some degree. These results reveal a contrasting effect of CP on anti-CTLA-4 therapy between the two mouse tumor models. Cyclophosphamide augments the antitumor effect of anti-CTLA-4 therapy in CT26-bearing hosts, whereas CP after anti-CTLA-4 therapy attenuates this effect through induction of apoptosis in tumor-reactive T cells. Alternatively, CP-induced MDSCs can be increased by anti-CTLA-4 therapy only in RENCA-bearing hosts with an elevated level of interleukin-6.

• 癌細胞のオートファジーと低酸素応答制御による免疫的細胞傷害抵抗性の克服2013 · 基盤研究(C)
• 免疫アジュバント受容体シグナルによる癌細胞死とオートファジー2011 · 若手研究(B)
• エピジェネティクス治療薬による腫瘍抗原発現とT細胞感受性の増強
• ペプチドワクチンに基づくT細胞感受性の増強と新しい抗腫瘍免疫療法の開発

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