UPS: Opportunities and challenges for gastric cancer treatment

Abstract

Gastric cancer remains the fourth most frequently diagnosed malignancy and the fifth leading cause of cancer-related mortality worldwide owning to the lack of efficient drugs and targets for therapy. Accumulating evidence indicates that UPS, which consists of E1, E2, and E3 enzymes and proteasome, plays an important role in the GC tumorigenesis. The imbalance of UPS impairs the protein homeostasis network during development of GC. Therefore, modulating these enzymes and proteasome may be a promising strategy for GC target therapy. Besides, PROTAC, a strategy using UPS to degrade the target protein, is an emerging tool for drug development. Thus far, more and more PROTAC drugs enter clinical trials for cancer therapy. Here, we will analyze the abnormal expression enzymes in UPS and summarize the E3 enzymes which can be developed in PROTAC so that it can contribute to the development of UPS modulator and PROTAC technology for GC therapy.

Keywords: E3 ligase; PROTAC; UPS modulator; gastric cancer; therapy.

Figure 1

Abnormal UPS affects the normal signaling pathways in cells, leading to or inhibiting the occurrence of gastric cancer.

Figure 2

UPS modulators inhibit gastric tumorigenesis by regulating the abnormal components of the UPS including proteasome, E1 enzymes, E2 enzymes (UBE2C, UBE2T, etc.), and E3 enzymes (MDM2, Cullin1, etc.).

Figure 3

PROTAC drugs degrade important oncogenic substrates in the process of tumorigenesis by linking the E3 enzyme and substrate (HUWE1/TGFBR2, FBXO31/SNAI1, ITCH/Smad7, etc.), preventing the occurrence of gastric cancer.