Yuki Suehiro1, Yoshihiro Takemoto2, Arata Nishimoto3, Koji Ueno1, Bungo Shirasawa4, Toshiki Tanaka1, Naruji Kugimiya1, Atsushi Suga1, Eijiro Harada1, Kimikazu Hamano1. 1. Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan. 2. Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan ytake@yamaguchi-u.ac.jp anishimo@yamaguchi-u.ac.jp. 3. Department of Medical Education, Yamaguchi University Graduate School of Medicine, Ube, Japan ytake@yamaguchi-u.ac.jp anishimo@yamaguchi-u.ac.jp. 4. Department of Medical Education, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Abstract
BACKGROUND/AIM: 5-Fluorouracil (5-FU) is frequently used in colorectal cancer treatment, but with limited success. The aim of the present study was to explore the cytotoxic effects of 5-FU, in combination with inhibition of doublecortin-like kinase 1 (Dclk1), a tumor stem cell marker that regulates pro-survival signaling in colorectal cancer cells, in the human colon cancer cell line, COLO-320. MATERIALS AND METHODS: The effects of 5-FU treatment plus Dclk1 inhibition on the phosphorylation of checkpoint kinase 1 (Chk1), cell cycle, DNA damage, apoptosis, and cell survival in COLO-320 cells were evaluated. RESULTS: Combined treatment with 5-FU and a Dclk1 inhibitor, LRRK2-IN-1 (LRRK), decreased 5-FU-induced phosphorylation of Chk1 and canceled 5-FU-induced cell-cycle arrest at the S phase. Combined treatment with 5-FU and LRRK failed to induce poly (ADP-ribose) polymerase 1 (PARP-1) cleavage, but tended to decrease cell survival compared to individual treatment with 5-FU or LRRK. CONCLUSION: These results indicate that a combination of 5-FU and LRRK may be an effective, novel approach for colorectal cancer therapy. Copyright
BACKGROUND/AIM: 5-Fluorouracil (5-FU) is frequently used in colorectal cancer treatment, but with limited success. The aim of the present study was to explore the cytotoxic effects of 5-FU, in combination with inhibition of doublecortin-like kinase 1 (Dclk1), a tumor stem cell marker that regulates pro-survival signaling in colorectal cancer cells, in the humancolon cancer cell line, COLO-320. MATERIALS AND METHODS: The effects of 5-FU treatment plus Dclk1 inhibition on the phosphorylation of checkpoint kinase 1 (Chk1), cell cycle, DNA damage, apoptosis, and cell survival in COLO-320 cells were evaluated. RESULTS: Combined treatment with 5-FU and a Dclk1 inhibitor, LRRK2-IN-1 (LRRK), decreased 5-FU-induced phosphorylation of Chk1 and canceled 5-FU-induced cell-cycle arrest at the S phase. Combined treatment with 5-FU and LRRK failed to induce poly (ADP-ribose) polymerase 1 (PARP-1) cleavage, but tended to decrease cell survival compared to individual treatment with 5-FU or LRRK. CONCLUSION: These results indicate that a combination of 5-FU and LRRK may be an effective, novel approach for colorectal cancer therapy. Copyright
Authors: Karsten Krug; Eric J Jaehnig; Shankha Satpathy; Lili Blumenberg; Alla Karpova; Meenakshi Anurag; George Miles; Philipp Mertins; Yifat Geffen; Lauren C Tang; David I Heiman; Song Cao; Yosef E Maruvka; Jonathan T Lei; Chen Huang; Ramani B Kothadia; Antonio Colaprico; Chet Birger; Jarey Wang; Yongchao Dou; Bo Wen; Zhiao Shi; Yuxing Liao; Maciej Wiznerowicz; Matthew A Wyczalkowski; Xi Steven Chen; Jacob J Kennedy; Amanda G Paulovich; Mathangi Thiagarajan; Christopher R Kinsinger; Tara Hiltke; Emily S Boja; Mehdi Mesri; Ana I Robles; Henry Rodriguez; Thomas F Westbrook; Li Ding; Gad Getz; Karl R Clauser; David Fenyö; Kelly V Ruggles; Bing Zhang; D R Mani; Steven A Carr; Matthew J Ellis; Michael A Gillette Journal: Cell Date: 2020-11-18 Impact factor: 41.582
Authors: Yan Liu; Fleur M Ferguson; Lianbo Li; Miljan Kuljanin; Caitlin E Mills; Kartik Subramanian; Wayne Harshbarger; Sudershan Gondi; Jinhua Wang; Peter K Sorger; Joseph D Mancias; Nathanael S Gray; Kenneth D Westover Journal: Cell Chem Biol Date: 2020-08-04 Impact factor: 8.116