Summary
Quiescent (G0) cells are transient cell-cycle-arrested subpopulations in cancers that include dormant cancer stem cells. While leukemic stem cells/minimal-residual-disease were studied transcriptionally, their translation profile and post-transcriptional mechanisms that control their proteome—and thereby, survival—are unknown. We find G0 leukemic cells are chemoresistant, with altered canonical translation and similar proteome and translatome—rather than transcriptome—to cells isolated post-chemotherapy, implicating post-transcriptional regulation in chemoresistance. Mechanistically, we find DNA-damage-responsive-ATM and stress-activated-p38-MAPK/MK2 alter post-transcriptional mechanisms, regulating mRNA-decay-factor, TTP, to increase AU-rich-element-bearing mRNAs. This permits translation of AU-rich-element-bearing pro-inflammatory-cytokine TNFα, and immune modulators that promote survival. Co-inhibiting p38-MAPK/MK2 and TNFα—prior to/alongwith chemotherapy—decreases chemoresistance in vivo. Disrupting TTP regulation reduces TNFα and chemoresistance, revealing TTP as a regulator of inflammation-mediated chemoresistance.
Significance Leukemic stem cells/minimal-residual-disease that are chemoresistant have been studied transcriptionally; however, their translation profile and post-transcriptional mechanisms that control their proteome and survival are unknown. Our data suggest that G0 cancer cells are chemoresistant. We find alternate post-transcriptional mechanisms in G0 cancer cells, which may regulate a distinct translatome to mediate their resistance. Our data uncover a pro-inflammatory subpopulation in cancer that enables chemoresistance via DNA-damage- and stress-regulated post-transcriptional mechanisms. These studies reveal the significance of post-transcriptional regulation of inflammatory/immune response in chemoresistance, mediated by AU-rich-elements, mRNA-decay-regulator TTP, and non-canonical translation. The results reveal DNA-damage/stress-induced TTP as a key regulator of inflammation-mediated chemoresistance and developed a new combination therapy to reduce resistance in cell lines, patient samples and in vivo.