Abstract
Clusterin is a secretory heterodimeric glycoprotein and the overexpression of secretory clusterin (sCLU) promotes cancer cell proliferation and reduces chemosensitivity. Therefore, sCLU might be an effective target for anticancer therapy. In the current study, we identified eIF3f as a novel CLU-interacting protein and demonstrated its novel function as a CLU inhibitor. The overexpression of eIF3f retarded cancer cell growth significantly and induced apoptosis. In addition, eIF3f interacted with the α-chain (1–227) of sCLU. This interaction blocked modification of psCLU, thereby decreasing the expression and secretion of α/β CLU. Consequently, the overexpression of eIF3f suppressed Akt and ERK signaling and subsequently depleted CLU expression. In addition, eIF3F stabilized p53, which increased the expression of p21 and Bax. Interestingly, the expression of Bax was increased without the activation of p53. eIF3f injected into a xenograft model of human cervical cancer in nude mice markedly inhibited tumor growth. The identification of this novel function of eIF3f as a sCLU inhibitor might open novel avenues for developing improved strategies for CLU-targeted anti-cancer therapies.
Highlights
Clusterin (CLU), known as apolipoprotein J (APO J), sulfated glycoprotein (SGP-2), or testosterone repressed prostate message-2 (TRPM-2), is a glycoprotein that acts in a variety of physiological processes such as the cell cycle, DNA repair, tissue remodeling, membrane recycling, lipid transport, immune system regulation, cell adhesion, and apoptosis [1,2,3,4,5]
CLU was used as the bait, and a human cDNA library was used as the prey, and the results revealed that eIF3f was a CLU binding partner
The upregulated expression of CLU was associated with highly aggressive breast carcinoma [9, 32] and with tumor progression and recurrence in bladder cancer [33]
Summary
Clusterin (CLU), known as apolipoprotein J (APO J), sulfated glycoprotein (SGP-2), or testosterone repressed prostate message-2 (TRPM-2), is a glycoprotein that acts in a variety of physiological processes such as the cell cycle, DNA repair, tissue remodeling, membrane recycling, lipid transport, immune system regulation, cell adhesion, and apoptosis [1,2,3,4,5]. SCLU is translated into a 60-kDa sCLU precursor protein (psCLU) from the first AUG codon. This protein is translocated directly into the endoplasmic reticulum (ER) by a leader signal peptide, where it is glycosylated and cleaved into α- and β-chains in the trans-Golgi compartments. The nCLU isoform is 55 kDa in size; it is generated initially as a 49-kDa nCLU precursor protein (pnCLU) from the second AUG codon by an alternative splicing event that eliminates exon II, which encodes the first AUG codon and signal peptide. PnCLU is located in the cytoplasm normally; it undergoes glycosylation to form the 55-kDa nCLU, which is translocated from the cytoplasm to the nucleus in response to cell damage [6, 7] Α/β cleavage and glycosylation do not occur. pnCLU is located in the cytoplasm normally; it undergoes glycosylation to form the 55-kDa nCLU, which is translocated from the cytoplasm to the nucleus in response to cell damage [6, 7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
