posted on 2021-10-04, 21:09authored byArielle Shkedi, Michael Adkisson, Andrew Schroeder, Walter L Eckalbar, Szu-Yu Kuo, Leonard Neckers, Jason E. Gestwicki
The
protein homeostasis (proteostasis) network is composed of multiple
pathways that work together to balance protein folding, stability,
and turnover. Cancer cells are particularly reliant on this network;
however, it is hypothesized that inhibition of one node might lead
to compensation. To better understand these connections, we dosed
22Rv1 prostate cancer cells with inhibitors of four proteostasis targets
(Hsp70, Hsp90, proteasome, and p97), either alone or in binary combinations,
and measured the effects on cell growth. The results reveal a series
of additive, synergistic, and antagonistic relationships, including
strong synergy between inhibitors of p97 and the proteasome and striking
antagonism between inhibitors of Hsp90 and the proteasome. Based on
RNA-seq, these relationships are associated, in part, with activation
of stress pathways. Together, these results suggest that cocktails
of proteostasis inhibitors might be a powerful way of treating some
cancers, although antagonism that blunts the efficacy of both molecules
is also possible.