Details of a Researcher - TAKADA Kouichi

Papers - TAKADA Kouichi

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Ofatumumab combined with chlorambucil for previously untreated chronic lymphocytic leukemia: a phase I/II, open-label study in Japan

Kiyohiko Hatake, Michinori Ogura, Kohichi Takada, Masafumi Taniwaki, Fanghong Zhang, Taizo Fujita, Kiyoshi Ando

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER JAPAN KK ) 106 ( 2 ) 240 - 247 2017.08 [Refereed]

Elderly/comorbid patients with chronic lymphocytic leukemia (CLL) require low-toxicity treatments. Internationally, the standard treatment for such patients is chlorambucil and an anti-CD20 therapy; however, chlorambucil is not approved in Japan. The aim of the present study was to evaluate the safety, efficacy and pharmacokinetics of ofatumumab in combination with chlorambucil in Japanese patients with previously untreated CLL who were inappropriate for fludarabine-based therapy. Ten patients were enrolled and treated in this study, all of whom received at least one dose of the study drugs. The tolerability of the treatment was confirmed initially with three patients. The overall response rate was 50%, as determined by the Independent Review Committee (IRC) with computerized tomography. All patients were alive at follow-up, and only one patient had progressive disease. The most common treatment-related adverse events (AEs) were thrombocytopenia (n = 10), neutropenia (n = 9) and rash (n = 6). One grade 3 serious AE related to the study drug occurred (hypoxia). The results indicate that ofatumumab combined with chlorambucil is an effective treatment for Japanese CLL patients, with a manageable safety profile.

DOI PubMed

Activated p53 with Histone Deacetylase Inhibitor Enhances L-Fucose-Mediated Drug Delivery through Induction of Fucosyltransferase 8 Expression in Hepatocellular Carcinoma Cells

Yutaka Okagawa, Kohichi Takada, Yohei Arihara, Shohei Kikuchi, Takahiro Osuga, Hajime Nakamura, Yusuke Kamihara, Naotaka Hayasaka, Makoto Usami, Kazuyuki Murase, Koji Miyanishi, Masayoshi Kobune, Junji Kato

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 11 ( 12 ) 2016.12 [Refereed]

Authorship： Lead author

Background The prognosis of advanced hepatocellular carcinoma (HCC) is dismal, underscoring the need for novel effective treatments. The alpha 1,6-fucosyltransferase (fucosyltransferase 8, FUT8) has been reported to accelerate malignant potential in HCC. Our study aimed to investigate the regulation of FUT8 expression by p53 and develop a novel therapeutic strategy for targeting HCC cells using L-fucose-mediated drug delivery. Methods Binding sites for p53 were searched for within the FUT8 promoter region. FUT8 expression was assessed by immunoblotting. Chromatin immunoprecipitation (ChIP) assays were performed to analyze p53 binding to the FUT8 promoter. The delivery of Cy5.5-encapsulated L-fucose-liposomes (Fuc-Lip-Cy5.5) to a Lens Culinaris agglutinin-reactive fraction of a-fetoprotein (AFP-L3)-expressing HCC cells was analyzed by flow cytometry. The induction of FUT8 by histone deacetylase inhibitor (HDACi) -inducing acetylated -p53 was evaluated by immunoblotting. Flow cytometric analysis was performed to assess whether the activation of p53 by HDACi affected the uptake of Fuc-Lip-Cy5.5 by HCC cells. The cytotoxicity of an L-fucose-bound liposome carrying sorafenib (Fuc-Lip-sorafenib) with HDACi was assessed in vivo and in vitro. Results The knock down of p53 with siRNA led to decreased FUT8 expression. ChIP assays revealed p53 binds to the FUT8 promoter region. Flow cytometric analyses demonstrated the specific uptake of Fuc-Lip-Cy5.5 into AFP-L3-expressing HCC cells in a p53- and FUT8- dependent manner. HDACi upregulated the uptake of Fuc-Lip-Cy5.5 by HCC cells by increasing FUT8 via acetylated -p53. The addition of a HDACi increased apoptosis induced by Fuc-Lip-sorafenib in HCC cells. Conclusions Our findings reveal that FUT8 is a p53 target gene and suggest that p53 activated by HDACi induces Fuc-Lip-sorafenib uptake by HCC cells, highlighting this pathway as a promising therapeutic intervention for HCC.

DOI

The iron chelator deferasirox induces apoptosis by targeting oncogenic Pyk2/β-catenin signaling in human multiple myeloma.

Yusuke Kamihara, Kohichi Takada, Tsutomu Sato, Yutaka Kawano, Kazuyuki Murase, Yohei Arihara, Shohei Kikuchi, Naotaka Hayasaka, Makoto Usami, Satoshi Iyama, Koji Miyanishi, Yasushi Sato, Masayoshi Kobune, Junji Kato

Oncotarget 7 ( 39 ) 64330 - 64341 2016.09 [Refereed] [International journal]

Authorship： Lead author

Deregulated iron metabolism underlies the pathogenesis of many human cancers. Recently, low expression of ferroportin, which is the only identified non-heme iron exporter, has been associated with significantly reduced overall survival in multiple myeloma (MM); however, the altered iron metabolism in MM biology remains unclear. In this study we demonstrated, by live cell imaging, that MM cells have increased intracellular iron levels as compared with normal cells. In experiments to test the effect of iron chelation on the growth of MM cells, we found that deferasirox (DFX), an oral iron chelator used to treat iron overload in clinical practice, inhibits MM cell growth both in vivo and in vitro. Mechanistically, DFX was found to induce apoptosis of MM cells via the inhibition of proline-rich tyrosine kinase 2 (Pyk2), which is known to promote tumor growth in MM. Inhibition of Pyk2 is caused by the suppression of reactive oxygen species, and leads to downregulation of the Wnt/β-catenin signaling pathway. Taken together, our findings indicate that high levels of intracellular iron, which might be due to low ferroportin expression, play a role in MM pathophysiology. Therefore, DFX may provide a therapeutic option for MM that is driven by deregulated iron homeostasis and/or Pyk2/Wnt signaling.

DOI PubMed

A role for peripherally inserted central venous catheters in the prevention of catheter-related blood stream infections in patients with hematological malignancies

Toshiro Sakai, Kyuhei Kohda, Yuichi Konuma, Yasuko Hiraoka, Yukari Ichikawa, Kaoru Ono, Hiroto Horiguchi, Ayumi Tatekoshi, Kouichi Takada, Satoshi Iyama, Junji Kato

International Journal of Hematology ( Springer Science and Business Media LLC ) 100 ( 6 ) 592 - 598 2014.12 [Refereed]

DOI

miR-30-5p Functions as a Tumor Suppressor and Novel Therapeutic Tool by Targeting the Oncogenic Wnt/beta-Catenin/BCL9 Pathway

Jian-Jun Zhao, Jianhong Lin, Di Zhu, Xujun Wang, Daniel Brooks, Ming Chen, Zhang-Bo Chu, Kohichi Takada, Bryan Ciccarelli, Samir Admin, Jianguo Tao, Yu-Tzu Tai, Steven Treon, Geraldine Pinkus, Winston Patrick Kuo, Teru Hideshima, Mary Bouxsein, Nikhil Munshi, Kenneth Anderson, Ruben Carrasco

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 74 ( 6 ) 1801 - 1813 2014.03 [Refereed]

Wnt/beta-catenin signaling underlies the pathogenesis of a broad range of human cancers, including the deadly plasma cell cancer multiple myeloma. In this study, we report that downregulation of the tumor suppressor microRNA miR-30-5p is a frequent pathogenetic event in multiple myeloma. Evidence was developed that miR-30-5p downregulation occurs as a result of interaction between multiple myeloma cells and bone marrow stromal cells, which in turn enhances expression of BCL9, a transcriptional coactivator of the Wnt signaling pathway known to promote multiple myeloma cell proliferation, survival, migration, drug resistance, and formation of multiple myeloma cancer stem cells. The potential for clinical translation of strategies to re-express miR-30-5p as a therapeutic approach was further encouraged by the capacity of miR-30c and miR-30 mix to reduce tumor burden and metastatic potential in vivo in three murine xenograft models of human multiple myeloma without adversely affecting associated bone disease. Together, our findings offer a preclinical rationale to explore miR-30-5p delivery as an effective therapeutic strategy to eradicate multiple myeloma cells in vivo. (C) 2014 AACR.

DOI PubMed

Successful Treatment with Entecavir for Reactivation of Hepatitis B Virus Following Systemic Chemotherapy in a Hepatitis B Surface Antigen-negative Patient with Colorectal Cancer

Yutaka Okagawa, Kohichi Takada, Hiroyuki Hisai, Yutaka Koshiba, Hironori Wada, Etsu Miyazaki, Yusuke Kanari, Yutaka Kawano, Satoshi Iyama, Tsuyoshi Hayashi, Tsutomu Sato, Yasushi Sato, Koji Miyanishi, Masayoshi Kobune, Rishu Takimoto, Junji Kato

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE ) 53 ( 16 ) 1759 - 1762 2014 [Refereed]

Reactivation of hepatitis B virus (HBV) has recently been reported as a fatal complication in patients undergoing cytotoxic chemotherapy. We herein describe a case of reactivation in a 76-year-old man who had undergone pelvic exenteration for colorectal cancer (CRC). He was treated with a modified FOLFOX6 chemotherapy regimen after the operation. Thirteen months later, his laboratory data showed severe liver dysfunction. His hepatitis B surface antigen (HBsAg) test was positive, and his HBV-DNA level was elevated. We diagnosed the patient with HBV reactivation as his HBsAg test was negative before starting chemotherapy. His liver dysfunction improved after administration of entecavir. This is the first report describing HBV reactivation following chemotherapy for an HBsAg-negative CRC patient.

DOI PubMed

TRIM13 (RFP2) downregulation decreases tumour cell growth in multiple myeloma through inhibition of NF Kappa B pathway and proteasome activity

Moshe E. Gatt, Kohichi Takada, Mala Mani, Mikael Lerner, Marjorie Pick, Teru Hideshima, Daniel E. Carrasco, Alexei Protopopov, Elena Ivanova, Olle Sangfelt, Dan Grander, Bart Barlogie, John D. Shaughnessy, Kenneth C. Anderson, Daniel R. Carrasco

BRITISH JOURNAL OF HAEMATOLOGY ( WILEY ) 162 ( 2 ) 210 - 220 2013.07 [Refereed]

Multiple myeloma (MM) is an incurable neoplasm caused by proliferation of malignant plasma cells in the bone marrow (BM). MM is characterized frequently by a complete or partial deletion of chromosome 13q14, seen in more than 50% of patients at diagnosis. Within this deleted region the tripartite motif containing 13 (TRIM13, also termed RFP2) gene product has been proposed to be a tumour suppressor gene (TSG). Here, we show that low expression levels of TRIM13 in MM are associated with chromosome 13q deletion and poor clinical outcome. We present a functional analysis of TRIM13 using a loss-of-function approach, and demonstrate that TRIM13 downregulation decreases tumour cell survival as well as cell cycle progression and proliferation of MM cells. In addition, we provide evidence for the involvement of TRIM13 downregulation in inhibiting the NF kappa B pathway and the activity of the 20S proteasome. Although this data does not support a role of TRIM13 as a TSG, it substantiates important roles of TRIM13 in MM tumour survival and proliferation, underscoring its potential role as a novel target for therapeutic intervention.

DOI PubMed

Targeted Disruption of the BCL9/beta-Catenin Complex Inhibits Oncogenic Wnt Signaling

Kohichi Takada, Di Zhu, Gregory H. Bird, Kumar Sukhdeo, Jian-Jun Zhao, Mala Mani, Madeleine Lemieux, Daniel E. Carrasco, Jeremy Ryan, David Horst, Mariateresa Fulciniti, Nikhil C. Munshi, Wenqing Xu, Andrew L. Kung, Ramesh A. Shivdasani, Loren D. Walensky, Daniel Ruben Carrasco

SCIENCE TRANSLATIONAL MEDICINE ( AMER ASSOC ADVANCEMENT SCIENCE ) 4 ( 148 ) 148ra117 2012.08 [Refereed]

Authorship： Lead author

Deregulated Wnt/beta-catenin signaling underlies the pathogenesis of a broad range of human cancers, yet the development of targeted therapies to disrupt the resulting aberrant transcription has proved difficult because the pathway comprises large protein interaction surfaces and regulates many homeostatic functions. Therefore, we have directed our efforts toward blocking the interaction of beta-catenin with B cell lymphoma 9 (BCL9), a coactivator for beta-catenin-mediated transcription that is highly expressed in tumors but not in the cells of origin. BCL9 drives beta-catenin signaling through direct binding mediated by its alpha-helical homology domain 2. We developed a stabilized a helix of BCL9 (SAH-BCL9), which we show targets beta-catenin, dissociates native beta-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and exhibits mechanism-based antitumor effects. SAH-BCL9 also suppresses tumor growth, angiogenesis, invasion, and metastasis in mouse xenograft models of Colo320 colorectal carcinoma and INA-6 multiple myeloma. By inhibiting the BCL9-beta-catenin interaction and selectively suppressing oncogenic Wnt transcription, SAH-BCL9 may serve as a prototype therapeutic agent for cancers driven by deregulated Wnt signaling.

DOI PubMed

β-catenin is dynamically stored and cleared in multiple myeloma by the proteasome–aggresome–autophagosome–lysosome pathway

K Sukhdeo, M Mani, T Hideshima, K Takada, V Pena-Cruz, G Mendez, S Ito, K C Anderson, D R Carrasco

Leukemia ( Springer Science and Business Media LLC ) 26 ( 5 ) 1116 - 1119 2012.05 [Refereed]

DOI

BCL9 Promotes Tumor Progression by Conferring Enhanced Proliferative, Metastatic, and Angiogenic Properties to Cancer Cells

Mala Mani, Daniel E. Carrasco, Yunyu Zhang, Kohichi Takada, Moshe E. Gatt, Jin Dutta-Simmons, Hiroshi Ikeda, Felipe Diaz-Griffero, Victor Pena-Cruz, Monica Bertagnolli, Lois L. Myeroff, Sanford D. Markowitz, Kenneth C. Anderson, Daniel R. Carrasco

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 69 ( 19 ) 7577 - 7586 2009.10 [Refereed]

Several components of the Writ signaling cascade have been shown to function either as tumor suppressor proteins or as oncogenes in multiple human cancers, underscoring the relevance of this pathway in oncogenesis and the need for further investigation of Wnt signaling components as potential targets for cancer therapy. Here, using expression profiling analysis as well as in vitro and in vivo functional studies,we show that the Writ pathway component BCL9 is a novel oncogene that is aberrantly expressed in human multiple myeloma as well as colon carcinoma. We show that BCL9 enhances beta-catenin-mediated transcriptional activity regardless of the mutational status of the Writ signaling components and increases cell proliferation, migration, invasion, and the metastatic potential of tumor cells by promoting loss of epithelial and gain of mesenchymal-like phenotype. Most importantly, BCL9 knockdown significantly increased the survival of xenograft mouse models of cancer by reducing tumor load, metastasis, and host angiogenesis through down-regulation of c-Myc, cyclin D1, CD44, and vascular endothelial growth factor expression by tumor cells. Together, these findings suggest that deregulation of BCL9 is an important contributing factor to tumor progression. The pleiotropic roles of BCL9 reported in this study underscore its value as a drug target for therapeutic intervention in several malignancies associated with aberrant Wnt signaling. [Cancer Res 2009;69(19):7577-86]

DOI PubMed

Aurora kinase A is a target of Wnt/beta-catenin involved in multiple myeloma disease progression

Jui Dutta-Simmons, Yunyu Zhang, Gullu Gorgun, Moshe Gatt, Mala Mani, Teru Hideshima, Kohichi Takada, Nicole E. Carlson, Daniel E. Carrasco, Yu-Tzu Tai, Noopur Raje, Anthony G. Letai, Kenneth C. Anderson, Daniel R. Carrasco

BLOOD ( AMER SOC HEMATOLOGY ) 114 ( 13 ) 2699 - 2708 2009.09 [Refereed]

Multiple myeloma (MM) is a cancer of plasma cells with complex molecular characteristics that evolves from monoclonal gammopathy of undetermined significance, a highly prevalent premalignant condition. MM is the second most frequent hematologic cancer in the United States, and it remains incurable, thereby highlighting the need for new therapeutic approaches, particularly those targeting common molecular pathways involved in disease progression and maintenance, shared across different MM subtypes. Here we report that Wnt/beta-catenin is one such pathway. We document the involvement of beta-catenin in cell-cycle regulation, proliferation, and invasion contributing to enhanced proliferative and metastatic properties of MM. The pleiotropic effects of beta-catenin in MM correlate with its transcriptional function, and we demonstrate regulation of a novel target gene, Aurora kinase A, implicating beta-catenin in G2/M regulation. beta-catenin and Aurora kinase A are present in most MM but not in normal plasma cells and are expressed in a pattern that parallels progression from monoclonal gammopathy of undetermined significance to MM. Our data provide evidence for a novel functional link between beta-catenin and Aurora kinase A, underscoring a critical role of these pathways in MM disease progression. (Blood. 2009; 114: 2699-2708)

DOI PubMed

Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone.

Sato Y, Murase K, Kato J, Kobune M, Sato T, Kawano Y, Takimoto R, Takada K, Miyanishi K, Matsunaga T, Takayama T, Niitsu Y

Nature biotechnology ( 4 ) 26 ( 4 ) 431 - 442 2008.04 [Refereed]

DOI PubMed

Efficacy of eribulin monotherapy for bone marrow carcinomatosis of breast cancer in a patient with Werner syndrome.

Akihito Fujimi, Yasuhiro Nagamachi, Naofumi Yamauchi, Riku Hasebe, Naoki Onoyama, Naotaka Hayasaka, Teppei Matsuno, Kazuhiko Koike, Yoshiro Gotoh, Kohji Ihara, Junji Kato, Takuji Nishisato, Kazuyuki Murase, Goro Kutomi, Tokimasa Hida, Hisashi Uhara, Kohichi Takada

Geriatrics & gerontology international 2025.01 [Domestic journal]

DOI PubMed

Establishment and characterization of the novel myxofibrosarcoma cell line, SMU-MFS

Naoya Nakahashi, Makoto Emori, Kohichi Takada, Yasutaka Murahashi, Junya Shimizu, Kazuyuki Murase, Tomohide Tsukahara, Shintaro Sugita, Akira Takasawa, Kousuke Iba, Atsushi Teramoto, Makoto Osanai

Human Cell ( Springer Science and Business Media LLC ) 38 ( 1 ) 2024.12

DOI

Secondary Osteosarcoma After Carbon‐Ion Radiotherapy for Desmoid‐Type Fibromatosis: A Case Report

Mizuki Aketo, Makoto Emori, Kohichi Takada, Kazuyuki Murase, Yohei Arihara, Junya Shimizu, Yasutaka Murahashi, Masahiko Okamoto, Shintaro Sugita, Atsushi Teramoto

Cancer Reports ( Wiley ) 7 ( 11 ) 2024.11

ABSTRACT Background Radiotherapy is considered an alternative treatment for unresectable or pharmacologically resistant desmoid‐type fibromatosis. While it results in relatively good local control, the risk of secondary malignancy remains a concern. Case We present a case of secondary osteosarcoma after carbon‐ion radiation therapy (CIRT). A 31‐year‐old male patient presented with left thigh pain. The tumor was located between the left gluteus maximus and gluteus medius and extended to the vastus lateralis and biceps femoris. It was diagnosed as desmoid‐type fibromatosis after needle biopsy. The patient was treated with several medications, including a cyclooxygenase 2 inhibitor and tamoxifen; however, his left thigh pain did not improve. He was treated with CIRT 1 year after diagnosis (67.2 Gy [relative biological effectiveness] 16fr/4wks). He developed osteosarcoma of the left femur 8 years later. He underwent chemotherapy and tumor excision with disarticulation of the left hip. Pulmonary metastasis was detected 6 and 17 months after the definitive surgery and excised using metastasectomy. However, he died due to the recurrence of multiple pulmonary metastases 29 months after the definitive surgery. Conclusions In this case, we believe that the low radiation dose to the femur may have caused secondary malignancy.

DOI

Application of Single Cell Type-Derived Spheroids Generated by Using a Hanging Drop Culture Technique in Various In Vitro Disease Models: A Narrow Review.

Hiroshi Ohguro, Megumi Watanabe, Tatsuya Sato, Nami Nishikiori, Araya Umetsu, Megumi Higashide, Toshiyuki Yano, Hiromu Suzuki, Akihiro Miyazaki, Kohichi Takada, Hisashi Uhara, Masato Furuhashi, Fumihito Hikage

Cells 13 ( 18 ) 2024.09 [International journal]

Cell culture methods are indispensable strategies for studies in biological sciences and for drug discovery and testing. Most cell cultures have been developed using two-dimensional (2D) culture methods, but three-dimensional (3D) culture techniques enable the establishment of in vitro models that replicate various pathogenic conditions and they provide valuable insights into the pathophysiology of various diseases as well as more precise results in tests for drug efficacy. However, one difficulty in the use of 3D cultures is selection of the appropriate 3D cell culture technique for the study purpose among the various techniques ranging from the simplest single cell type-derived spheroid culture to the more sophisticated organoid cultures. In the simplest single cell type-derived spheroid cultures, there are also various scaffold-assisted methods such as hydrogel-assisted cultures, biofilm-assisted cultures, particle-assisted cultures, and magnet particle-assisted cultures, as well as non-assisted methods, such as static suspension cultures, floating cultures, and hanging drop cultures. Since each method can be differently influenced by various factors such as gravity force, buoyant force, centrifugal force, and magnetic force, in addition to non-physiological scaffolds, each method has its own advantages and disadvantages, and the methods have different suitable applications. We have been focusing on the use of a hanging drop culture method for modeling various non-cancerous and cancerous diseases because this technique is affected only by gravity force and buoyant force and is thus the simplest method among the various single cell type-derived spheroid culture methods. We have found that the biological natures of spheroids generated even by the simplest method of hanging drop cultures are completely different from those of 2D cultured cells. In this review, we focus on the biological aspects of single cell type-derived spheroid culture and its applications in in vitro models for various diseases.

DOI PubMed

切除不能または再発胆道癌に対するゲムシタビン/シスプラチン/S-1(GCS)療法とゲムシタビン/シスプラチン/デュルバルマブ(GCD)療法との比較検討

吉田真誠, 村松丈児, 石川和真, 高田弘一, 村瀬和幸, 大沼啓之, 柾木喜晴, 永島裕之, 宮西浩嗣

胆道 ( (一社)日本胆道学会 ) 38 ( 3 ) 421 - 421 2024.09

Novel method for assessing sinusoidal obstruction syndrome using four‐dimensional computed tomography

Saori Shimoyama‐Ibuki, Satoshi Iyama, Yoshiya Ohashi, Kento Ono, Yusuke Sugama, Chisa Fujita, Akari Goto, Hiroto Horiguchi, Akihito Fujimi, Takeo Tanaka, Kohichi Takada, Koh‐Ichi Sakata, Masayoshi Kobune

eJHaem ( Wiley ) 2024.07

Abstract Introduction To diagnose sinusoidal obstruction syndrome/veno‐occlusive disease (SOS/VOD), transabdominal ultrasonography is usually used to detect hemodynamic changes, but we tried to detect the changes using four‐dimensional computed tomography (4D‐CT). A 42‐year‐old Japanese woman was diagnosed with late‐onset SOS/VOD with transabdominal ultrasonography and was also assessed using 4D‐CT. Method We analyzed the portal vein (PV) contrast effect every 1.5 seconds and plotted the values of the contrast effect. With this graph, we analyzed three hemodynamic parameters. Result We found that these parameters correlated with the patient's status and indicated stasis due to sinusoid constriction. Conclusion 4D‐CT may become a helpful tool to diagnose and follow up with SOS/VOD.

DOI

Modulation of Epithelial-Mesenchymal Transition Is a Possible Underlying Mechanism for Inducing Chemoresistance in MIA PaCa-2 Cells against Gemcitabine and Paclitaxel.

Hajime Nakamura, Megumi Watanabe, Kohichi Takada, Tatsuya Sato, Fumihito Hikage, Araya Umetsu, Joji Muramatsu, Masato Furuhashi, Hiroshi Ohguro

Biomedicines 12 ( 5 ) 2024.05 [International journal]

To elucidate the currently unknown molecular mechanisms responsible for the similarity and difference during the acquirement of resistance against gemcitabine (GEM) and paclitaxel (PTX) in patients with pancreatic carcinoma, we examined two-dimensional (2D) and three-dimensional (3D) cultures of parent MIA PaCa-2 cells (MIA PaCa-2-PA) and their GEM resistance cell line (MIA PaCa-2-GR) and PTX resistance (MIA PaCa-2-PR). Using these cells, we examined 3D spheroid configurations and cellular metabolism, including mitochondrial and glycolytic functions, with a Seahorse bio-analyzer and RNA sequencing analysis. Compared to the MIA PaCa-2-PA, (1) the formation of the 3D spheroids of MIA PaCa-2-GR or -PR was much slower, and (2) their mitochondrial and glycolytic functions were greatly modulated in MIA PaCa-2-GR or -PR, and such metabolic changes were also different between their 2D and 3D culture conditions. RNA sequencing and bioinformatic analyses of the differentially expressed genes (DEGs) using an ingenuity pathway analysis (IPA) suggested that various modulatory factors related to epithelial -mesenchymal transition (EMT) including STAT3, GLI1, ZNF367, NKX3-2, ZIC2, IFIT2, HEY1 and FBLX, may be the possible upstream regulators and/or causal network master regulators responsible for the acquirement of drug resistance in MIA PaCa-2-GR and -PR. In addition, among the prominently altered DEGs (Log2 fold changes more than 6 or less than -6), FABP5, IQSEC3, and GASK1B were identified as unique genes associated with their antisense RNA or pseudogenes, and among these, FABP5 and GASK1B are known to function as modulators of cancerous EMT. Therefore, the observations reported herein suggest that modulations of cancerous EMT may be key molecular mechanisms that are responsible for inducing chemoresistance against GEM or PTX in MIA PaCa-2 cells.

DOI PubMed

Stage IVa進行食道癌におけるDocetaxel/CDGP/5-FU・放射線同時併用療法(DNF-R)の予後解析

佐藤昌則, 大沼啓之, 早坂尚貴, 濱口孝太, 村瀬和幸, 高田弘一, 宮西浩嗣, 加藤淳二, 染谷正則, 坂田耕一

北海道医学雑誌 ( 北海道医学会 ) 98 ( 2 ) 139 - 139 2023.11

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Papers - TAKADA Kouichi