MDM4 expression as an indicator of TP53 reactivation by combined targeting of MDM2 and MDM4 in cancer cells without TP53 mutation

Abstract

MDM2 and MDM4, a structurally related MDM2 homolog, negatively regulates expression and functions of TP53 tumor suppressor gene. To explore the precise expression patterns and function of MDM2 and MDM4 in wild-type (wt) TP53 cancer cells, we analyzed 11 various cancer cell lines with wt TP53. All cell lines exhibited deregulated expression of MDM2 and MDM4, and were divided into two distinct types; the one expressing high levels of MDM4 and another expressing low levels of MDM4. The low MDM4 type expressed higher MDM2 levels than the high MDM4 type. In cells with high MDM4 expression, knockdown of MDM4 or MDM2 reactivated TP53, and simultaneous knockdown of MDM2 and MDM4 synergistically reactivated TP53. In contrast, in cells with low MDM4 expression, knockdown of only MDM2 reactivated TP53. These results suggest that both MDM2 and MDM4 are closely involved in TP53 inactivation in cancer cells with high MDM4 expression, whereas only MDM2, and not MDM4, is a regulator of TP53 in cells with low MDM4 expression. MDM4 expression in wt TP53-tumors is a potential indicator for TP53 reactivation cancer therapy by simultaneous targeting of MDM4 and MDM2. Specific knockdown of MDM2 and MDM4 might be applicable for TP53 restoration therapy.

Augmented antitumor activity of 5‐fluorouracil by double knockdown of MDM4 and MDM2 in colon and gastric cancer cells

“…In our previous study, simultaneous knockdown of MDM4 and MDM2 using synthetic DNA-substituted siRNAs (chiMDM4 and chiMDM2) was shown to synergistically suppress the growth of cancer cells with wtTP53/ highMDM4. 16 In this study, we showed that double knockdown of MDM4 and MDM2 enhanced the antitumor activity of 5-FU in colon and gastric cancer cells with wtTP53/highMDM4.…”

“…A previous study reported that cultured tumor cells with wt TP53 can be divided into 2 types: high MDM2 expressers and high MDM4 expressers . The former expresses a high level of MDM2 and a very low level of MDM4, whereas the latter expresses a high level of MDM4 and an intermediate level of MDM2.…”

“…Studies have shown that reactivation of wild‐type (wt) TP53 by inhibiting MDM2‐p53 interaction or knockdown of MDM2 and MDM4 induces cell cycle arrest and apoptotic cell death, inhibiting tumor growth in tumors carrying wt TP53 . Thus, MDM2 and MDM4 are ideal targets for cancer therapy in such tumors.…”

“…11,12 Studies have shown that reactivation of wild-type (wt) TP53 by inhibiting MDM2-p53 interaction or knockdown of MDM2 and MDM4 induces cell cycle arrest and apoptotic cell death, inhibiting tumor growth in tumors carrying wtTP53. 6,[13][14][15][16][17][18][19] Thus, MDM2 and MDM4 are ideal targets for cancer therapy in such tumors. Various kinds of small molecular compounds and peptides inhibiting MDM2 function have been developed.…”

“…[22][23][24] A previous study reported that cultured tumor cells with wtTP53 can be divided into 2 types: high MDM2 expressers and high MDM4 expressers. 16 Overexpression or amplification of MDM4 has been found in 19%-49% and 43% of colon and gastric cancers, respectively, whereas those of MDM2 have been reported in 17.3% and 32.7%-41.8% of colon and gastric cancers, respectively. [25][26][27][28][29] Therefore, reactivation of wtTP53 by chiMDM4 and chiMDM2 could be used for the treatment of these cancers.…”