“…[49][50][51][52][53] The combined inhibition of both UCHL5 and USP14 results in lethality, indicates their nonredundancy, and suggests their role in maintaining cancer cell survival, which partly explains the finding that b-AP15, which selectively disrupts both USP14 and UCHL5 activity, was shown to significantly increase cancer cell apoptosis in vitro and to inhibit tumor progression, as well as exhibit robust antitumor activity. [54][55][56] Anti-cancer activity of IU1 is associated with growth arrest through inhibition of deubiquitilating activity of USP14, downregulation of COPS5, and upregulation of p53-dependent p21, p15, and beclin-1 and p53-independent COPS5 downstream effects AP-1, E2F1, p27, and cyclin E1, as well as induction of caspase-dependent apoptosis. Additionally, the effects of IU1 were shown to be independent of p53 status, as well as the expression of BCL-2, both of which can influence the response to bortezomib therapy.…”