Abstract
Understanding the determination of cell fate choices after cancer treatment will shed new light on cancer resistance. In this study, we quantitatively analyzed the individual cell fate choice in resistant UM-SCC-38 head and neck cancer cells exposed to cisplatin. Our study revealed a highly heterogeneous pattern of cell fate choices in UM-SCC-38 cells, in comparison to that of the control, non-tumorigenic keratinocyte HaCaT cells. In both UM-SCC-38 and HaCaT cell lines, the majority of cell death occurred during the immediate interphase without mitotic entry, whereas significant portions of UM-SCC-38 cells survived the treatment via either checkpoint arrest or checkpoint slippage. Interestingly, checkpoint slippage occurred predominantly in cells treated in late S and G2 phases, and cells in M-phase were hypersensitive to cisplatin. Moreover, although the cisplatin-resistant progression of mitosis exhibited no delay in general, prolonged mitosis was correlated with the induction of cell death in mitosis. The finding thus suggested a combinatorial treatment using cisplatin and an agent that blocks mitotic exit. Consistently, we showed a strong synergy between cisplatin and the proteasome inhibitor Mg132. Finally, targeting the DNA damage checkpoint using inhibitors of ATR, but not ATM, effectively sensitized UM-SCC-38 to cisplatin treatment. Surprisingly, checkpoint targeting eliminated both checkpoint arrest and checkpoint slippage, and augmented the induction of cell death in interphase without mitotic entry. Taken together, our study, by profiling cell fate determination after cisplatin treatment, reveals new insights into chemoresistance and suggests combinatorial strategies that potentially overcome cancer resistance.
Highlights
Genotoxic agents are often utilized in cancer therapy because these drugs cause DNA damage, which, in turn, induce apoptosis and other cell death pathways [1, 2]
UM-SCC-38 cell line was selected because this head and neck squamous cell carcinoma (HNSCC) has been previously characterized to be resistant to cisplatin treatment [10, 11]
Mitotic cell death has been implicated in chemotherapy, e.g. via mitotic catastrophe, it did not appear to play a significant role in the treatment of UM-SCC-38 cells with cisplatin
Summary
Genotoxic agents are often utilized in cancer therapy because these drugs cause DNA damage, which, in turn, induce apoptosis and other cell death pathways [1, 2]. The therapeutic benefit of chemotherapy is limited in many clinical cases due to intrinsic or acquired resistance of tumor cells to DNA damage. It has been suggested that targeting the cellular DNA damage response (DDR) may offer a valuable tool to improve the therapeutic window and effectiveness of chemotherapy [3, 4]. The efficacy of cisplatin in these other solid tumors appears less satisfactory, as many tumors either exhibit resistance to cisplatin or relapse despite initial response [5, 6]
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