A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells.

Abstract

BACKGROUND:

Quiescence (G0) is a transient, cell cycle-arrested state. By entering G0, cancer cells survive unfavorable conditions such as chemotherapy and cause relapse. While G0 cells have been studied at the transcriptome level, how post-transcriptional regulation contributes to their chemoresistance remains unknown.

RESULTS:

We induce chemoresistant and G0 leukemic cells by serum starvation or chemotherapy treatment. To study post-transcriptional regulation in G0 leukemic cells, we systematically analyzed their transcriptome, translatome, and proteome. We find that our resistant G0 cells recapitulate gene expression profiles of in vivo chemoresistant leukemic and G0 models. In G0 cells, canonical translation initiation is inhibited; yet we find that inflammatory genes are highly translated, indicating alternative post-transcriptional regulation. Importantly, AU-rich elements (AREs) are significantly enriched in the upregulated G0 translatome and transcriptome. Mechanistically, we find the stress-responsive p38 MAPK-MK2 signaling pathway stabilizes ARE mRNAs by phosphorylation and inactivation of mRNA decay factor, Tristetraprolin (TTP) in G0. This permits expression of ARE mRNAs that promote chemoresistance. Conversely, inhibition of TTP phosphorylation by p38 MAPK inhibitors and non-phosphorylatable TTP mutant decreases ARE-bearing TNFα and DUSP1 mRNAs and sensitizes leukemic cells to chemotherapy. Furthermore, co-inhibiting p38 MAPK and TNFα prior to or along with chemotherapy substantially reduces chemoresistance in primary leukemic cells ex vivo and in vivo.

CONCLUSIONS:

These studies uncover post-transcriptional regulation underlying chemoresistance in leukemia. Our data reveal the p38 MAPK-MK2-TTP axis as a key regulator of expression of ARE-bearing mRNAs that promote chemoresistance. By disrupting this pathway, we develop an effective combination therapy against chemosurvival.

• Authors: Sooncheol Lee, Douglas Micalizzi, Samuel S Truesdell, Syed I A Bukhari, Myriam Boukhali, Jennifer Lombardi-Story, Yasutaka Kato, Min-Kyung Choo, Ipsita Dey-Guha, Fei Ji, Benjamin T Nicholson, David T Myers, Dongjun Lee, Maria A Mazzola, Radhika Raheja, Adam Langenbucher, Nicholas J Haradhvala, Michael S Lawrence, Roopali Gandhi, Christopher Tiedje, Manuel D Diaz-Muñoz, David A Sweetser, Ruslan Sadreyev, David Sykes, Wilhelm Haas, Daniel A Haber, Shyamala Maheswaran, Shobha Vasudevan
• Journal: Genome biology (Genome Biol) Vol. 21 Issue 1 Pg. 33 (02 10 2020) ISSN: 1474-760X [Electronic] England
• PMID: 32039742 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Proteome
• Tristetraprolin
• Tumor Necrosis Factor-alpha
• ZFP36 protein, human
• MAP-kinase-activated kinase 2
• Protein Serine-Threonine Kinases
• p38 Mitogen-Activated Protein Kinases
• DUSP1 protein, human
• Dual Specificity Phosphatase 1

Topics

• AU Rich Elements
• Animals
• Cell Cycle
• Cells, Cultured
• Drug Resistance, Neoplasm
• Dual Specificity Phosphatase 1 (genetics, metabolism)
• Hep G2 Cells
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• K562 Cells
• MCF-7 Cells
• Mice
• Mice, Inbred C57BL
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proteome (genetics, metabolism)
• RNA Processing, Post-Transcriptional
• THP-1 Cells
• Transcriptome
• Tristetraprolin (genetics, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• p38 Mitogen-Activated Protein Kinases (genetics, metabolism)