Maintenance of endoplasmic reticulum homeostasis in
5-FU resistant Hela cells
The changes of chaperone-mediated
folding play an important role in tumorigenesis and the evolution of
drug resistance mechanisms (Jarosz, 2016). Based on proteomic profiling,
we found that the most significant difference in protein synthesis,
processing and transport between 2D monolayer cultures and 3D MTSs was
mainly enriched in the ER, which was dominated by the heat shock protein
family, including HYOU1, HSPA5, HSP90B1, HSPG2 (Figure. 5A-D ).
Compared with 2D monolayer cultures, changes in the tumor
microenvironment and metabolic rearrangement of tumor cells in 3D MTSs
would affect protein processing (Mischiati et al.,
2015). It was shown that hypoxia
areas in tumor, nutritional deficiency, pH gradient, and disorder of
calcium ion homeostasis could promote unfolded protein response (UPR) to
activate the ER stress response (Ron & Walter, 2007). UPR signaling can
contribute to maintaining proper protein folding function under the ER
stress, but the mechanism of apoptosis would be triggered when the cells
were exposed to ER stress for a long time and the ER function was
impaired (Hoyer-Hansen & Jaattela, 2007). We observed an up-regulation
of protein folding, which contributes to the maintenance of ER
homeostasis (Table S3 and Table S4 ). Pavan et al.
showed that disrupting ER homeostasis by increasing the concentration of
calcium ion could induce the death of tumor cells (Pavan Grandhi, Potta,
Nitiyanandan, Deshpande, & Rege, 2017). Thus, the maintenance of ER
homeostasis in 3D MTSs may be one of the major reasons for the increased
drug resistance to 5-FU.