The Impact of Pdcd4, a Translation Inhibitor, on Drug Resistance

Abstract

Programmed cell death 4 (Pdcd4) is a tumor suppressor, which has been demonstrated to efficiently suppress tumorigenesis. Biochemically, Pdcd4 binds with translation initiation factor 4A and represses protein translation. Beyond its role in tumor suppression, growing evidence suggests that Pdcd4 enhances the chemosensitivity of several anticancer drugs. To date, numerous translational targets of Pdcd4 have been identified. These targets govern important signal transduction pathways, and their attenuation may improve chemosensitivity or overcome drug resistance. This review will discuss the signal transduction pathways regulated by Pdcd4 and the potential mechanisms through which Pdcd4 enhances chemosensitivity or counteracts drug resistance.

Keywords: IGF1R/IR inhibitor; JNK pathway; doxorubicin; eIF4A; fluorouracil; mTORC2–Akt pathway; paclitaxel; platinum-containing drug; β-catenin pathway.

Figure 1

Pdcd4 is a tumor suppressor. Experimental evidence has shown that Pdcd4 suppresses various cancer cell characteristics including inflammation, proliferation, survival, invasion, and metastasis. Additionally, Pdcd4 promotes apoptosis and helps to overcome drug resistance.

Figure 2

Schematic diagram of the functional motifs of Pdcd4. Two MA-3 domains binding with eIF4A to inhibit protein translation; Ser67 phosphorylated by Akt or p70S6K for proteasome degradation; Ser457 phosphorylated by Akt for nuclear localization; Arg110 methylated by PRMT5 to attenuate the tumor suppression function; the positive amino acid cluster (+++) binding with RNAs.

Figure 3

Pdcd4 suppresses mTORC2–Akt pathway.

Figure 4

Pdcd4 suppresses the E-cadherin–β-catenin pathway. The transcription repressor Snail suppresses E-cadherin expression, leading to β-catenin nuclear translocation and binding with Tcf4 to stimulate expression of oncogenes and chemoresistance genes.

Figure 5

Pdcd4 suppresses JNK–AP-1 pathway. Pdcd4 inhibits MAP4K1 expression or directly binds to c-Jun, resulting in suppression of JNK–AP-1 pathway.