Integrated imaging and proteomics sensors detect proteome aggregation induced by platinum-based chemotherapy drugs in living cells and mice model

Abstract

Proteome aggregation is challenging to analyze given its loss of defined 3-D structures to develop chemo- and bio-sensors. Herein, we present integrated chemical sensors to image the occurrence of proteome aggregation and dissect its proteomic composition. Via these combinative sensors, we systematically reveal for the first time platinum-based drugs can deteriorate proteome stability, compromise protein homeostasis (proteostasis) network, and consequently cause proteome aggregation. Fluorescent protein aggregation imaging sensors (AggStain and AggRetina) not only confirms these drugs generally induce intracellular proteome aggregation but also quantifies the compactness (polarity) heterogeneity inside these aggregates. Chemical proteomics sensor (AggLink) further captures and profiles the composition of aggregated proteome, which uncovers the fluctuations of proteostasis network and metabolic pathways. In mice model, proteome aggregation and oxidative stress are imaged in multi-organs with platinum enrichment. Together, we integrate imaging and proteomics sensors to provide an alternative mechanism-of-action for platinum-based drugs’ anti-cancer function in addition to their common DNA intercalation mechanism.