Cell-cycle fate-monitoring distinguishes individual chemosensitive and chemoresistant cancer cells in drug-treated heterogeneous populations demonstrated by real-time FUCCI imaging |
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Authors: | Shinji Miwa Shuya Yano Hiroaki Kimura Mako Yamamoto Makoto Toneri Yasunori Matsumoto Fuminari Uehara Yukihiko Hiroshima Takashi Murakami Katsuhiro Hayashi Norio Yamamoto Michael Bouvet Toshiyoshi Fujiwara Hiroyuki Tsuchiya Robert M Hoffman |
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Affiliation: | 1.AntiCancer; Inc.; San Diego, CA USA;2.Department of Surgery; University of California; San Diego, CA USA;3.Department of Orthopedic Surgery; Kanazawa University Graduate School of Medical Sciences; Kanazawa, Ishikawa, Japan;4.Division of Surgical Oncology; Department of Surgery; Okayama University Graduate School of Medicine; Dentistry and Pharmaceutical Sciences; Okayama, Japan |
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Abstract: | Essentially every population of cancer cells within a tumor is heterogeneous, especially with regard to chemosensitivity and resistance. In the present study, we utilized the fluorescence ubiquitination-based cell cycle indicator (FUCCI) imaging system to investigate the correlation between cell-cycle behavior and apoptosis after treatment of cancer cells with chemotherapeutic drugs. HeLa cells expressing FUCCI were treated with doxorubicin (DOX) (5 μM) or cisplatinum (CDDP) (5 μM) for 3 h. Cell-cycle progression and apoptosis were monitored by time-lapse FUCCI imaging for 72 h. Time-lapse FUCCI imaging demonstrated that both DOX and CDDP could induce cell cycle arrest in S/G2/M in almost all the cells, but a subpopulation of the cells could escape the block and undergo mitosis. The subpopulation which went through mitosis subsequently underwent apoptosis, while the cells arrested in S/G2/M survived. The present results demonstrate that chemoresistant cells can be readily identified in a heterogeneous population of cancer cells by S/G2/M arrest, which can serve in future studies as a visible target for novel agents that kill cell-cycle-arrested cells. |
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Keywords: | cancer cell cycle chemoresistance chemosensitivity cisplatinum doxorubicin FUCCI GFP RFP HeLa time-lapse imaging tumor heterogeneity |
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