Article Abstract

Targeting liquid-liquid phase separation in pancreatic cancer

Authors: Yue Ming, Xia Chen, Yuanpei Xu, Yuanyuan Wu, Chenlu Wang, Tingting Zhang, Renfang Mao, Yihui Fan

Abstract

Background: Accumulated evidence suggests a critical role of protein-mediated liquid-liquid phase separation (LLPS) in many key biological processes through organization of membrane-less compartments. However, the pathological role of protein-mediated LLPS remains elusive and it is unknown whether protein-mediated LLPS contributes to carcinogenesis.
Methods: HPDE6-C7, BxPC-3, PANC-1, AsPC-1 and CFPAC-1 cells were treated with the LLPS inhibitor, 1,6-hexanediol. Cell proliferation was determined by CCK8 assay. An atopic BxPC-3 xenograft mouse model was established and treated with 1,6-hexanediol. Gene expression profiling was achieved by RNA-sequencing.
Results: 1,6-hexanediol significantly inhibited cell proliferation and induced cell death in all tested pancreatic cancer cells (BxPC-3, PANC-1, AsPC-1 and CFPAC-1) but had a minimal effect on control cells (HPDE6-C7) at low doses. In an atopic BxPC-3 xenograft model, 1,6-hexanediol significantly limited pancreatic cancer growth. In whole genomic transcriptional analysis, 1,6-hexanediol significantly downregulated the expression of a set of genes that were enriched in cytokine-cytokine receptor interactions, WNT signaling pathway, ECM-receptor interaction, MAPK signaling pathway and focal adhesion. Furthermore, 1,6-hexanediol treatment specifically reduced the expression of MYC but not IL-6 and KLF5.
Conclusions: Together, we provided evidence to demonstrate an important role of protein-mediated LLPS in pancreatic cancer. Cancer cells might be more addictive to LLPS and thus disruption of such a process might be a novel way to treat cancer.