PDCD4 interacting with PIK3CB and CTSZ promotes the apoptosis of multiple myeloma cells.

Publisher: Federation of American Societies for Experimental Biology Country of Publication: United States NLM ID: 8804484 Publication Model: Print Cited Medium: Internet ISSN: 1530-6860 (Electronic) Linking ISSN: 08926638 NLM ISO Abbreviation: FASEB J Subsets: MEDLINE

Publication: 2020- : [Bethesda, Md.] : Hoboken, NJ : Federation of American Societies for Experimental Biology ; Wiley
Original Publication: [Bethesda, Md.] : The Federation, [c1987-

Apoptosis* ; Apoptosis Regulatory Proteins*/genetics ; Apoptosis Regulatory Proteins*/metabolism ; Multiple Myeloma*/metabolism ; Multiple Myeloma*/genetics ; Multiple Myeloma*/pathology ; RNA-Binding Proteins*/metabolism ; RNA-Binding Proteins*/genetics; Animals ; Humans ; Male ; Mice ; Cell Line, Tumor ; Class I Phosphatidylinositol 3-Kinases/metabolism ; Class I Phosphatidylinositol 3-Kinases/genetics ; Gene Expression Regulation, Neoplastic ; X-Linked Inhibitor of Apoptosis Protein/metabolism ; X-Linked Inhibitor of Apoptosis Protein/genetics

The role of programmed cell death 4 (PDCD4) in multiple myeloma (MM) development remains unknown. Here, we investigated its role and action mechanism in MM. Bioinformatic analysis indicated that patients with MM and high PDCD4 expression had higher overall survival than those with low PDCD4 expression. PDCD4 expression promoted MM cell apoptosis and inhibited their viability in vitro and tumor growth in vivo. RNA-binding protein immunoprecipitation sequencing analysis showed that PDCD4 is bound to the 5' UTR of the apoptosis-related genes PIK3CB, Cathepsin Z (CTSZ), and X-chromosome-linked apoptosis inhibitor (XIAP). PDCD4 knockdown reduced the cell apoptosis rate, which was rescued by adding PIK3CB, CTSZ, or XIAP inhibitors. Dual luciferase reporter assays confirmed the internal ribosome entry site (IRES) activity of the 5' UTRs of PIK3CB and CTSZ. An RNA pull-down assay confirmed binding of the 5' UTR of PIK3CB and CTSZ to PDCD4, identifying the specific binding fragments. PDCD4 is expected to promote MM cell apoptosis by binding to the IRES domain in the 5' UTR of PIK3CB and CTSZ and inhibiting their translation. Our findings suggest that PDCD4 plays an important role in MM development by regulating the expression of PIK3CB, CTSZ, and XIAP, and highlight new potential molecular targets for MM treatment.
(© 2024 Federation of American Societies for Experimental Biology.)

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CXGC011101 Key Technology Research and Development Program of Shandong Province (Key Technology R&D Program of Shandong Province); 11681803 Weihai Zhengsheng Biotechnology Foundation; ZR2020MH123 National Natural Science Foundation of China (NSFC)

Keywords: Cathepsin Z; PIK3CB; apoptosis; multiple myeloma; programmed cell death 4

0 (Apoptosis Regulatory Proteins)
EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
0 (PDCD4 protein, human)
0 (RNA-Binding Proteins)
0 (X-Linked Inhibitor of Apoptosis Protein)
EC 3.4.18.1 (CTSZ protein, human)
EC 2.7.1.137 (PIK3CB protein, human)

Date Created: 20240827 Date Completed: 20240827 Latest Revision: 20240904

20240904

10.1096/fj.202400687R

39190024