Fig. 5: Chk1 inhibition initiates caspase-activation in sensitive cell lines and increased chromosomal breakage in moderately sensitive cells. | Oncogenesis

Fig. 5: Chk1 inhibition initiates caspase-activation in sensitive cell lines and increased chromosomal breakage in moderately sensitive cells.

From: Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death

Fig. 5

a Sensitive HNSCC cell lines UM-SCC-22A and UM-SCC-38 harbor high levels of caspase 3/7 activity after 24 h of Chk1 inhibition. Induction of necrosis was observed in HNSCC cell lines VU-SCC-120 and FaDu, which is related to death in mitosis, whereas VU-SCC-096 showed both necrosis and some apoptosis. Responses were dose-dependent. b After CHEK1 knockdown (red bars), sensitive cell line UM-SCC-22A expresses increased caspase 3/7 activity 48 h after transfection. This was not observed in less-sensitive cell line VU-SCC-096 in accordance with small molecule inhibition with LY2603618/Rabusertib. Untransfected (green bars) and siCONTROL#2 (orange bars) conditions were included as controls. c Caspase 2 is an initiator of apoptotic cell death, and was found to be activated in UM-SCC-22A, likely because of the high levels of DNA damage (Fig. S5a). This cell line also showed the highest caspase 3/7 activity upon Chk1 inhibition and knockdown (Fig. 5a, b and S4c). d Metaphase cells exhibited a high number of chromosomal breaks in both sensitive as moderately sensitive cell lines. However, mitotic cells could not be scored for UM-SCC-22A after 1.5 µM LY2303618/Rabusertib treatment for 24 h, indicating pre-mitotic cell death in line with the findings from the live-cell imaging. The number of chromosomal breaks in VU-SCC-096 upon Chk1 inhibition is in line with mitotic cell death observed with live-cell imaging and is considered to be lethal for any cell

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