Abstract
Sorafenib and lenvatinib are approved first-line targeted therapies for advanced liver cancer, but most patients develop acquired resistance. Herein, we found that sorafenib induced extensive acetylation changes towards a more energetic metabolic phenotype. Metabolic adaptation was mediated via acetylation of the Lys-491 (K491) residue of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) (PCK2–K491) and Lys-473 (K473) residue of PCK1 (PCK1–K473) by the lysine acetyltransferase 8 (KAT8), resulting in isoenzyme transition from cytoplasmic PCK1 to mitochondrial PCK2. KAT8-catalyzed PCK2 acetylation at K491 impeded lysosomal degradation to increase the level of PCK2 in resistant cells. PCK2 inhibition in sorafenib-resistant cells significantly reversed drug resistance in vitro and in vivo. High levels of PCK2 predicted a shorter progression-free survival time in patients who received sorafenib treatment. Therefore, acetylation-induced isoenzyme transition from PCK1 to PCK2 contributes to resistance to systemic therapeutic drugs in liver cancer. PCK2 may be an emerging target for delaying tumor recurrence.
Original language | English |
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Pages (from-to) | 46-62 |
Number of pages | 17 |
Journal | Cancer Letters |
Volume | 519 |
DOIs | |
State | Published - Oct 28 2021 |
Keywords
- Acetylproteomics
- Lysine acetyltransferase 8
- Lysosome-related protein degradation
- Metabolic adaptation
- Phosphoenolpyruvate carboxykinase isoform 2
- Phosphoproteomics
- Protein acetylation
- Protein posttranslational modifications
- Sorafenib resistance