The effect of ubiquitination and deubiquitination to imatinib resistance in gastrointestinal stromal tumors

Abstract

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor. Imatinib, as a receptor-type tyrosine kinase inhibitor (TKI), becomes a first-line drug for adjuvant therapy and prognosis. However, patients are facing with the problem of primary and secondary drug resistance when using imatinib, which affects the effect of imatinib. Thus, it is particularly important to explore the mechanism of drug resistance. Ubiquitination and deubiquitination process have been proofed to performance as posttranslational modifications (PTMs) to influence the occurrence and progression of most tumors. Hence, we attach importance to these mechanisms and found that GIST resistance may be related to ubiquitination and deubiquitination in regulating exosome secretion, autophagy, apoptosis and ferroptosis. Through clarifying these connections, this review aims to offers insights and hope for therapeutic advancements of imatinib-resistant GIST patients and the use of specific ubiquitin modifications as markers in the future.

Keywords: deubiquitination modification; drug resistance; gastrointestinal stromal tumors; imatinib; ubiquitination modifications.

Figure 1

The process of ubiquitination. Ubiquitin protein is adenylytized at the C-terminal by E1 ubiquitin-activating enzyme, and then transferred from the cysteine residue at the active site of the E2 ubiquitin-conjugated enzyme to the lysine residue of the substrate protein, which is linked to the isopeptide bond between the lysine residue in the substrate protein by the action of E3 ubiquitin ligase.

Figure 2

The relationship between GIST progression and ubiquitination and deubiquitination system. (A) Imatinib induces BIM transcription through the PI3K-AKT-FOXO 3a pathway and the ubiquitination and phosphorylation levels of BIM are also reduced through MAPK signaling pathway which prevent the degradation of BIM then cause the apoptosis of tumor cells. (B) With internalization of c-KIT engulfed by clathrin, Cbl can modify c-KIT which result in the c-KIT degradation in lysosomes and causes apoptosis of tumor cells as well. (C) Imatinib, in GIST can promote ubiquitination of the K191 site of GPX 4 by promoting the expression of STIP1 homology and u-box containing protein 1 (STUB 1), leading to degradation of GPX 4 protein and inducing ferroptosis.

Figure 3

Imatinib resistance with the ubiquitination and deubiquitination of GISTs. (A) ETV1 can bind to two potential ETV 1 binding site upstream the USP32 promoter thus promoting polycystic transport by regulating the expression and localization of Rab35 through USP32 which can reduce the polyubiquitination of Rab35. With the help of Rab35, exosome secretion in GIST cells is upregulated which causes the resistance of imatinib in GIST cells to be transmitted. (B) Insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) can read METTL3-mediated m6A modification thus stabilizing USP13 mRNA, while USP13 can work as a deubiquitination protein that deubiquitinate UB molecules attached to ATG5 and causes protective autophagy of GIST cells. (C) FBXW7 can target the phosphorylated MCL1 molecule which leads to the degradation of MCL1, thereby relieving the inhibition of apoptosis and showing increased sensitivity to imatinib. (D) TRIM21 promotes the degradation of ACSL 4 by using a K48-linked polyubiquitin chain to lead to drug resistance, while ubiquitin-specific protease 15 (USP 15) upregulates the stability of ACSL 4 molecules through its deubiquitination activity and promotes ferroptosis in GIST cells to against resistance.