Abstract
The blockade of entering the cell cycle represents a hallmark of chemoresistant cancer cells, especially in chemoresistant cancer stem cells. Cell cycle blockade in quiescent cancer (stem) cells is largely attributed to the natural dormant behaviour of stem cells, and in a natural state the quiescent stem cells respond to stimuli rapidly for activation. Thus, eliminating quiescent chemoresistant cancer (stem) cells by extrinsic stimuli that promote entry into cell cycle provides a potential strategy for overcoming chemoresistance. Lung cancer cells were treated with or without IL6 before cDDP chemotherapy and a lung cancer patient derived single cell ex-vivo system and mice xenograft in-vivo model were developed. Here we report that in lung adenocarcinoma the interleukin 6 (IL6) treatment resulted in the expansion of cancer stem cells (EpCAM+/CD133+/CD44+/CD24-) and reduction of quiescent cancer (stem) cells (Hoechst 33342 and Pyronin γ double negative population, G0 cells) in several primary lung adenocarcinoma patient-derived primary lung cancer cells. IL6 pre-treatment increased cDDP chemosensitivity in lung adenocarcinoma by promoting quiescent lung cancer (stem) cells to enter the cell cycle. In parallel, we showed a mechanism for regulating the sensitivity of the IL6-STAT3 pathway to IL6 treatment, by ChIP-PCR and duo-luciferase reporter assay we identified an AP2 transcription factor TFAP2A activates the expression of IL6 receptor transcriptionally in lung cancer cell lines. Moreover, using a mice tail vein xenograft in vivo chemotherapy model with lung cancer cell lines, we report that IL6 pre-treatment significantly induced more cell death in platinum-based chemotherapy. Our data indicate that IL6 contributes to quiescent lung cancer (stem) cells entering the cell cycle, which significantly undermines chemoresistance and introduces a considerable clinical approach for platinum-based chemotherapy in lung adenocarcinoma.
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