Understanding of the anti-apoptotic mechanisms in senescent cells

• Project/Area Number: 24650625
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: HARA Eiji 公益財団法人がん研究会, がん研究所がん生物部, 部長 (80263268)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 癌 / 遺伝子 / シグナル伝達 / 老化 / 発現制御 / 細胞老化 / アポトーシス / 発がん / 国際情報交換 / 発癌

Outline of Final Research Achievements

We have tried to identify a promising molecular target that can be used to design interventions to promote apoptosis in senescent cells. By screening of a low molecular weight compound library, we found that a series of chemical inhibitors against the same histone modifying enzyme can provoke apoptosis in senescent, but not in non-senescent, human diploid fibroblasts. Similar results were also observed when we used several other human cell types, suggesting that this histone modifying enzyme plays a key role in preventing apoptosis in senescent human cells.

Research Products

• [Journal Article] In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line. (2015)
  • Author(s): Nanjo S, Yano S, et al.
  • Journal Title: Cancer Sci Volume: 106 Issue: 3 Pages: 244-52
  • DOI: 10.1111/cas.12600
  • NAID: 120005830611
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Evidence for a CDK4-dependent checkpoint in a conditional model of cellular senescence. (2015)
  • Author(s): Brookes S, Gagrica S, Sanij E, Rowe J, Gregory FJ, Hara E, and *Peters G.
  • Journal Title: Cell Cycle Volume: 14 Issue: 8 Pages: 1164-1173
  • DOI: 10.1080/15384101.2015.1010866
  • Peer Reviewed / Open Access
• [Journal Article] Dysregulation of the Bmi-1/p16Ink4a pathway provokes an aging-associated decline of submandibular gland function. (2015)
  • Author(s): Yamakoshi K, Katano S, Iida M, Kimura H, Okuma A, Ikemoto-Uezumi M, Ohtani N, Hara E, Maruyama M.
  • Journal Title: Aging Cell Volume: - Issue: 4 Pages: 1-9
  • DOI: 10.1111/acel.12337
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Ablation of the p16INK4a tumour suppressor reverses ageing phenotypes of klotho mice (2015)
  • Author(s): Seidai Sato, Yuka Kawamata, Akiko Takahashi, Yoshinori Imai, Aki Hanyu, Atsushi Okuma, Masaki Takasugi, Kimi Yamakoshi, Hiroyuki Sorimachi, Hiroaki Kanda, Yuichi Ishikawa, Saburo Sone, Yasuhiko Nishioka, Naoko Ohtani and Eiji Hara
  • Journal Title: Nature communications Volume: 6 Issue: 1 Pages: 7035-7035
  • DOI: 10.1038/ncomms8035
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Crosstalk between the RB-pathway and AKT signalling forms a Quiescence-Senescence switch. (2014)
  • Author(s): Imai, Y., Takahashi, A., Hanyuu, A., Hori, S., Sato, S., Naka, K., Hirao, A., Ohtani, N., Hara, E.
  • Journal Title: Cell Reports Volume: 7 Issue: 1 Pages: 194-207
  • DOI: 10.1016/j.celrep.2014.03.006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Obesity and Cancer: a gut microbial connection (2014)
  • Author(s): Ohtani, N.
  • Journal Title: Cancer Research Volume: 74 Issue: 7 Pages: 1885-11889
  • DOI: 10.1158/0008-5472.can-13-3501
  • Peer Reviewed
• [Journal Article] Necessary and sufficient role for a mitosis skip in senescence induction. (2014)
  • Author(s): Johmura Y, Shimada M, Misaki T, Naiki-Ito A, Miyoshi H, Motoyama N, Ohtani N, Hara E, Nakamura M, Morita A, Takahashi S, Nakanishi M.
  • Journal Title: Mol.Cell Volume: 55 Issue: 1 Pages: 73-84
  • DOI: 10.1016/j.molcel.2014.05.003
  • Peer Reviewed
• [Journal Article] An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. (2014)
  • Author(s): Demaria, M., Ohtani, N., Youssef, S.A., Rodier, F., Toussaint, W., Mitchell, J.R., Laberge, R.M., Vijg, J., Van Steeg, H., Dollé, M.E.T., Hoeijmakers, J.H.J., de Bruin, A., Hara, E.., Campisi, J.
  • Journal Title: Developmental Cell Volume: 31 Issue: 6 Pages: 722-733
  • DOI: 10.1016/j.devcel.2014.11.012
  • Peer Reviewed
• [Journal Article] Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome (2013)
  • Author(s): Yoshimoto, S.
  • Journal Title: Nature Volume: 499 Issue: 7456 Pages: 97-101
  • DOI: 10.1038/nature12347
  • Peer Reviewed
• [Journal Article] Protein Kinase A Determines Timing of Early Differentiation through Epigenetic Regulation with G9a (2012)
  • Author(s): Yamamizu K, Fujihara M, Tachibana M, Katayama S, Takahashi A, Hara E, Imai H, Shinkai Y, and Yamashita JK
  • Journal Title: Cell Stem Cell Volume: 10 Issue: 6 Pages: 759-770
  • DOI: 10.1016/j.stem.2012.02.022
  • Peer Reviewed
• [Presentation] 細胞老化の発がん制御における役割 (2015)
  • Author(s): 原 英二
  • Organizer: ヒューマンサイエンス総合研究セミナー
  • Place of Presentation: 東京
  • Year and Date: 2015-01-13
  • Invited
• [Presentation] The roles of cellular senescence in aging and cancer (2014)
  • Author(s): Akiko Takahashi & Eiji Hara
  • Organizer: 日本分子生物学会シンポジウム
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2014-11-25 – 2014-11-27
  • Invited
• [Presentation] 細胞老化による発がん制御 (2014)
  • Author(s): 原 英二
  • Organizer: 肺リモデリング研究会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-08
  • Invited
• [Presentation] 細胞老化反応の生体内イメージング (2014)
  • Author(s): 大熊敦史、大谷直子、山越貴水、原 英二
  • Organizer: 日本生化学会シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-17
  • Invited
• [Presentation] Crosstalk between the Rb-pathway and AKT signaling forms a Quiescence- Senescence switch (2014)
  • Author(s): Eiji Hara
  • Organizer: 日本癌学会コアシンポジウム
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] 細胞老化と癌：細胞老化の功罪 (2014)
  • Author(s): 原 英二
  • Organizer: 高遠・分子細胞生物学シンポジウム
  • Place of Presentation: 長野県伊那市
  • Year and Date: 2014-08-28 – 2014-08-29
  • Invited
• [Presentation] 細胞老化と炎症 (2014)
  • Author(s): 原 英二
  • Organizer: 日本動脈硬化学会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-10 – 2014-07-12
  • Invited
• [Presentation] 細胞老化と炎症 (2014)
  • Author(s): 原 英二
  • Organizer: 炎症・再生医学会シンポジウム
  • Place of Presentation: 沖縄県名護市
  • Year and Date: 2014-07-01 – 2014-07-03
  • Invited
• [Presentation] The roles and mechanisms of cellular senescence (2014)
  • Author(s): Eiji Hara
  • Organizer: 日本基礎老化学会国際シンポジウム
  • Place of Presentation: 愛知県大府市
  • Year and Date: 2014-06-26 – 2014-06-27
  • Invited
• [Presentation] 細胞老化と発癌 (2014)
  • Author(s): 原 英二
  • Organizer: 日本臨床分子医学会 シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2014-04-12 – 2014-04-13
  • Invited
• [Presentation] Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome (2013)
  • Author(s): Hara, E.
  • Organizer: 17th International Symposium on Cell of the Hepatic Sinusoid.
  • Place of Presentation: 大阪市
  • Invited
• [Presentation] The roles of cellular senescence in cancer and aging. (2012)
  • Author(s): 原 英二
  • Organizer: 日本分子生物学会
  • Place of Presentation: 福岡
  • Invited