Proteomics Analysis of Interactions between Drug-Resistant and Drug-Sensitive Cancer Cells: Comparative Studies of Monoculture and Coculture Cell Systems

Cell–cell interactions, which allow cells to communicate
with each other through molecules in their microenvironment, are critical
for the growth, health, and functions of cells. Previous studies show
that drug-resistant cells can interact with drug-sensitive cells to
elevate their drug resistance level, which is partially responsible
for cancer recurrence. Studying protein targets and pathways involved
in cell–cell communication provides essential information for
fundamental cell biology studies and therapeutics of human diseases.
In the current studies, we performed direct coculture and indirect
coculture of drug-resistant and drug-sensitive cell lines, aiming
to investigate intracellular proteins responsible for cell communication.
Comparative studies were carried out using monoculture cells. Shotgun
bottom-up proteomics results indicate that the P53 signaling pathway
has a strong association with drug resistance mechanisms, and multiple
TP53-related proteins were upregulated in both direct and indirect
coculture systems. In addition, cell–cell communication pathways,
including the phagosome and the HIF-signaling pathway, contribute
to both direct and indirect coculture systems. Consequently, AK3 and
H3–3A proteins were identified as potential targets for cell–cell
interactions that are relevant to drug resistance mechanisms. We propose
that the P53 signaling pathway, in which mitochondrial proteins play
an important role, is responsible for inducing drug resistance through
communication between drug-resistant and drug-sensitive cancer cells.