A specialized post‐transcriptional program in chemoresistant, quiescent cancer cells
Authors: Vasudevan Shobha , Lee Sooncheol , Micalizzi Douglas , Bukhari Syed Irfan Ahmad , Truesdell Samuel Spencer , Boukhali Myriam , Lombardi‐Story Jennifer , Dey‐Guha Ipsita , Choo Min‐Kyung , Mazzola Maria A , Raheja Radhika , Langenbucher Adam , Haradhwala Nicholas J , Lawrence Michael , Gandhi Roopali , Sweetser David , Sykes David , Haas Wilhelm , Haber Daniel , Maheswaran Shyamala 
Published: June 2021

Quiescent (G0) cells are a relevant fraction in cancers, which include dormant stem cells, and resist clinical therapy. G0 cells reveal 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 mRNAs to alter gene expression—associate with a key RNA‐binding protein, and recruit non‐canonical translation factors to mediate specific mRNA translation in G0. We find that G0 leukemic cells show similar proteome and translatome to cells isolated post‐chemotherapy. These data suggest that specialized post‐transcriptional mechanisms in G0 leukemic cells produce a distinct translatome to facilitate chemoresistance.

To understand post‐transcriptional regulation in chemoresistance, we compared global transcriptome, translatome and proteome in chemoresistant G0 acute monocytic leukemic (AML) cells. We find that chemotherapy or G0 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 modifying canonical translation. AREs are present on 3′UTRs of tightly regulated cytokines to post‐transcriptionally control their expression. Both rate limiting steps—tRNA recruitment and mRNA cap recognition—in canonical translation are altered. Stress signaling activates kinases that reduce canonical tRNA recruitment. This signaling also reduces mTOR activity in G0 and chemoresistant cells, which activates the cap complex inhibitor, eIF4EBP to impair canonical translation, leading to non‐canonical translation of specific mRNAs with specialized cap binding and ribosome recruitment factors.

These changes permit translation of ARE bearing pro‐inflammatory cytokine TNFα, and immune modulators that promote survival. Co‐inhibiting p38 MAPK and TNFα that promote anti‐apoptosis— prior to or along with chemotherapy—decreases chemoresistance in AML cells, in vivo, and in patient samples, without affecting normal cells. Our studies reveal a pro‐inflammatory subpopulation in AML that mediates resistance, 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, the ARE RNA binding protein and non‐canonical translation as regulators of chemoresistance. These studies reveal the importance of post‐transcriptional regulation of pro‐inflammatory genes in chemoresistance.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.