A Post‐Transcriptional Program of Chemoresistance Regulators in Quiescent Cancer Cells
Authors: Vasudevan Shobha , Lee Sooncheol , Bukhari Syed Irfan Ahmad , Truesdell Samuel Spencer , Boukhali Myriam , Lee Dongjun , Mazzola Maria A. , Raheja Radhika , Langenbucher Adam , Haradhvala Nicholas J. , Lawrence Michael , Gandhi Roopali , Sweetser David , Haas Wilhelm 
Published: June 2021

Quiescent (G0) cells are a clinically relevant fraction in several cancers, which include dormant cancer stem cells, and resist clinical therapy. G0 cells reveal extensive changes in gene expression at the protein and translation levels. We previously identified that the translation mechanism is altered in G0 cancer cells. MicroRNAs, noncoding RNAs that target distinct mRNAs to alter gene expression—were found to associate with an important RNA‐binding protein, and enable specialized functions in G0—where they recruit non‐canonical translation factors to regulate specific mRNA translation. We find that G0 leukemic cells show similar proteome and translatome to cells isolated post‐chemotherapy. These data suggest that specialized post‐transcriptional and translational mechanisms in G0 leukemic cells regulate a distinct translatome to mediate chemoresistance.

To understand the role of post‐transcriptional and translational regulation in chemoresistance, we compared global RNA, translational and proteome profiling in chemoresistant G0 acute monocytic leukemic (AML) cells. We find that chemotherapy or G0 induction leads to DNA damage responsive ATM and stress signaling, which alter post‐transcriptional and translational mechanisms. ATM and stress activated p38 MAPK/MK2 increase AU‐rich‐element (ARE) bearing pro‐inflammatory cytokine and immune gene mRNAs by regulating a key ARE RNA binding protein, and by activating STAT1/interferon pathway to alter canonical translation. AREs are present on 3′UTRs of critical, tightly regulated oncogenes and cytokines to post‐transcriptionally control their expression. These changes permit translation of ARE bearing pro‐inflammatory cytokine TNFα, and immune and cell‐migration modulators that promote survival. Co‐inhibiting p38 MAPK and TNFα that promote anti‐apoptosis—prior to or along with chemotherapy—decreases chemoresistance in AML cell lines, in vivo, and in patient samples, without affecting normal cells. These studies reveal a pro‐inflammatory subpopulation in AML that mediates chemoresistance, enabled by DNA damage‐ and stress‐regulated post‐transcriptional and translational mechanisms that are mediated by AU‐rich‐elements and a critical ARE RNA binding protein. Disrupting ARE regulation reduces TNFα and chemoresistance, revealing AREs and an important ARE RNA binding protein as key regulators of inflammation‐mediated chemoresistance. These studies reveal the significance of post‐transcriptional regulation of inflammation/immune gene‐mediated chemoresistance.

Support or Funding Information

The study is funded by Cancer Research Institute, D. & M‐E Ryder, Leukemia & Lymphoma Society, Smith Family Foundation, & NIGMS grants to SV. SL was funded by Fund for Medical Discovery fellowship & by a postdoctoral fellowship from the Basic Science Research Program of the National Research Foundation of Korea.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.