You are here

    • You are here:
    • Home > Events > PRBB-CRG Sessions Shobha Vasudevan

PRBB-CRG Sessions Shobha Vasudevan

PRBB-CRG Sessions Shobha Vasudevan

PRBB-CRG Sessions Shobha Vasudevan

05/10/2018
Add to Calendar
MARIE CURIE

05/10/201812:00MARIE CURIEPRBB-CRG SessionsShobha VasudevanMGH, Harvard University US"A specialized post-transcriptional program in chemoresistant, quiescent cancer cells"Host: Fátima Gebauer (CRG)Abstract:Quiescent (G0) cells are a clinically relevant fraction in 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 a key 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 mechanisms in G0 leukemic cells regulate a distinct translatome to mediate chemoresistance.
To understand the role of post-transcriptional regulation in chemoresistance, we compared global transcriptome, translatome 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 modifying canonical translation. AREs are present on 3’UTRs of tightly regulated oncogenes and cytokines, to post-transcriptionally control their expression. Both rate limiting steps—mRNA cap recognition and tRNA recruitment—in canonical translation are altered. These signaling pathways lead to low mTOR activity in G0, 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. In addition, stress and STAT1/interferon signaling activate kinases that reduce the canonical tRNA recruitment mechanism, enabling non-canonical translation of specific mRNAs.
These changes permit translation of ARE bearing pro-inflammatory cytokine TNFa, and immune and cell-migration modulators that promote survival. Co-inhibiting p38 MAPK and TNFa 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 TNFa and chemoresistance, revealing AREs, an important ARE RNA binding protein and non-canonical translation as regulators of chemoresistance. These studies reveal the significance of post-transcriptional regulation of pro-inflammatory and immune gene-mediated chemoresistance.