TY - JOUR
T1 - The imidazoacridinone C-1311 induces p53-dependent senescence or p53-independent apoptosis and sensitizes cancer cells to radiation
AU - Skwarska, Anna
AU - Ramachandran, Shaliny
AU - Dobrynin, Grzegorz
AU - Leszczynska, Katarzyna B.
AU - Hammond, Ester M.
N1 - Publisher Copyright:
© Skwarska et al.
PY - 2017
Y1 - 2017
N2 - C-1311 is a small molecule, which has shown promise in a number of preclinical and clinical studies. However, the biological response to C-1311 exposure is complicated and has been reported to involve a number of cell fates. Here, we investigated the molecular signaling which determines the response to C-1311 in both cancer and non-cancer cell lines. For the first time we demonstrate that the tumor suppressor, p53 plays a key role in cell fate determination after C-1311 treatment. In the presence of wild-type p53, cells exposed to C-1311 entered senescence. In contrast, cells lines without functional p53 underwent mitotic catastrophe and apoptosis. C-1311 also induced autophagy in a non-p53-dependent manner. Cells in hypoxic conditions also responded to C-1311 in a p53-dependent manner, suggesting that our observations are physiologically relevant. Most importantly, we show that C-1311 can be effectively combined with radiation to improve the radiosensitivity of a panel of cancer cell lines. Together, our data suggest that C-1311 warrants further clinical testing in combination with radiotherapy for the treatment of solid tumors.
AB - C-1311 is a small molecule, which has shown promise in a number of preclinical and clinical studies. However, the biological response to C-1311 exposure is complicated and has been reported to involve a number of cell fates. Here, we investigated the molecular signaling which determines the response to C-1311 in both cancer and non-cancer cell lines. For the first time we demonstrate that the tumor suppressor, p53 plays a key role in cell fate determination after C-1311 treatment. In the presence of wild-type p53, cells exposed to C-1311 entered senescence. In contrast, cells lines without functional p53 underwent mitotic catastrophe and apoptosis. C-1311 also induced autophagy in a non-p53-dependent manner. Cells in hypoxic conditions also responded to C-1311 in a p53-dependent manner, suggesting that our observations are physiologically relevant. Most importantly, we show that C-1311 can be effectively combined with radiation to improve the radiosensitivity of a panel of cancer cell lines. Together, our data suggest that C-1311 warrants further clinical testing in combination with radiotherapy for the treatment of solid tumors.
KW - Apoptosis
KW - C-1311/Symadex
KW - P53
KW - Radiation
KW - Senescence
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U2 - 10.18632/oncotarget.16102
DO - 10.18632/oncotarget.16102
M3 - Article
C2 - 28415717
AN - SCOPUS:85019133458
SN - 1949-2553
VL - 8
SP - 31187
EP - 31198
JO - Oncotarget
JF - Oncotarget
IS - 19
ER -