Inauhzin(c) Inactivates C-Myc Independently of P53

Overview

Journal Cancer Biol Ther

Specialties Oncology
Pharmacology

Date 2015 Feb 19

PMID 25692307

Citations 9

Authors

Ji Hoon Jung

Jun-Ming Liao

Qi Zhang

Shelya Zeng

Daniel Nguyen

Qian Hao

Xiang Zhou

Bo Cao

Sung-Hoon Kim

Hua Lu

Affiliations

Soon will be listed here.

Abstract

Oncogene MYC is deregulated in many human cancers, especially in lymphoma. Previously, we showed that inauhzin (INZ) activates p53 and inhibits tumor growth. However, whether INZ could suppress cancer cell growth independently of p53 activity is still elusive. Here, we report that INZ(c), a second generation of INZ, suppresses c-Myc activity and thus inhibits growth of human lymphoma cells in a p53-independent manner. INZ(c) treatment decreased c-Myc expression at both mRNA and protein level, and suppressed c-Myc transcriptional activity in human Burkitt's lymphoma Raji cells with mutant p53. Also, we showed that overexpressing ectopic c-Myc rescues the inhibition of cell proliferation by INZ(c) in Raji cells, implicating c-Myc activity is targeted by INZ(c). Interestingly, the effect of INZ(c) on c-Myc expression was impaired by disrupting the targeting of c-Myc mRNA by miRNAs via knockdown of ribosomal protein (RP) L5, RPL11, or Ago2, a subunit of RISC complex, indicating that INZ(c) targets c-Myc via miRNA pathways. These results reveal a new mechanism that INZ

Citing Articles

Acetylcorynoline Induces Apoptosis and G2/M Phase Arrest through the c-Myc Signaling Pathway in Colon Cancer Cells.

Park Y, Jee W, Park S, Kim S, Jung J, Kim H Int J Mol Sci. 2023; 24(24).

PMID: 38139419 PMC: 10744070. DOI: 10.3390/ijms242417589.

RNA-binding motif protein 10 inactivates c-Myc by partnering with ribosomal proteins uL18 and uL5.

Lee H, Jung J, Ko H, Park H, Segall A, Sheffmaker R Proc Natl Acad Sci U S A. 2023; 120(49):e2308292120.

PMID: 38032932 PMC: 10710042. DOI: 10.1073/pnas.2308292120.

The Antitumor Effect of Timosaponin A3 through c-Myc Inhibition in Colorectal Cancer Cells and Combined Treatment Effect with 5-FU or Doxorubicin.

Ko H, Jee W, Park D, Kim K, Jung J, Jang H Int J Mol Sci. 2022; 23(19).

PMID: 36233202 PMC: 9569550. DOI: 10.3390/ijms231911900.

CNOT2 Is Critically Involved in Atorvastatin Induced Apoptotic and Autophagic Cell Death in Non-Small Cell Lung Cancers.

Lee J, Jung J, Hwang J, Park J, Kim J, Park W Cancers (Basel). 2019; 11(10).

PMID: 31574980 PMC: 6826547. DOI: 10.3390/cancers11101470.

Current understanding of the role and regulation of miRNAs in Burkitt lymphoma.

Videtta A, Malagnino V, De Falco G Blood Lymphat Cancer. 2019; 8:33-45.

PMID: 31360092 PMC: 6467348. DOI: 10.2147/BLCTT.S129618.

References

Flores I, Murphy D, Swigart L, Knies U, Evan G . Defining the temporal requirements for Myc in the progression and maintenance of skin neoplasia. Oncogene. 2004; 23(35):5923-30. DOI: 10.1038/sj.onc.1207796. View

Honda R, Yasuda H . Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J. 1999; 18(1):22-7. PMC: 1171098. DOI: 10.1093/emboj/18.1.22. View

Pelengaris S, Littlewood T, Khan M, Elia G, Evan G . Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol Cell. 1999; 3(5):565-77. DOI: 10.1016/s1097-2765(00)80350-0. View

Felsher D, Bishop J . Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell. 1999; 4(2):199-207. DOI: 10.1016/s1097-2765(00)80367-6. View

Chendrimada T, Gregory R, Kumaraswamy E, Norman J, Cooch N, Nishikura K . TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature. 2005; 436(7051):740-4. PMC: 2944926. DOI: 10.1038/nature03868. View

Haase A, Jaskiewicz L, Zhang H, Laine S, Sack R, Gatignol A . TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing. EMBO Rep. 2005; 6(10):961-7. PMC: 1369185. DOI: 10.1038/sj.embor.7400509. View

Matranga C, Tomari Y, Shin C, Bartel D, Zamore P . Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell. 2005; 123(4):607-20. DOI: 10.1016/j.cell.2005.08.044. View

Dai M, Zeng S, Jin Y, Sun X, David L, Lu H . Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition. Mol Cell Biol. 2004; 24(17):7654-68. PMC: 506971. DOI: 10.1128/MCB.24.17.7654-7668.2004. View

Jin A, Itahana K, Okeefe K, Zhang Y . Inhibition of HDM2 and activation of p53 by ribosomal protein L23. Mol Cell Biol. 2004; 24(17):7669-80. PMC: 506972. DOI: 10.1128/MCB.24.17.7669-7680.2004. View

10.

Pomerantz M, Ahmadiyeh N, Jia L, Herman P, Verzi M, Doddapaneni H . The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat Genet. 2009; 41(8):882-4. PMC: 2763485. DOI: 10.1038/ng.403. View

11.

Lal A, Navarro F, Maher C, Maliszewski L, Yan N, ODay E . miR-24 Inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to "seedless" 3'UTR microRNA recognition elements. Mol Cell. 2009; 35(5):610-25. PMC: 2757794. DOI: 10.1016/j.molcel.2009.08.020. View

12.

Dang C, Le A, Gao P . MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 2009; 15(21):6479-83. PMC: 2783410. DOI: 10.1158/1078-0432.CCR-09-0889. View

13.

Christoffersen N, Shalgi R, Frankel L, Leucci E, Lees M, Klausen M . p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC. Cell Death Differ. 2009; 17(2):236-45. DOI: 10.1038/cdd.2009.109. View

14.

Wright J, Brown S, Cole M . Upregulation of c-MYC in cis through a large chromatin loop linked to a cancer risk-associated single-nucleotide polymorphism in colorectal cancer cells. Mol Cell Biol. 2010; 30(6):1411-20. PMC: 2832500. DOI: 10.1128/MCB.01384-09. View

15.

Gerin I, Bommer G, McCoin C, Sousa K, Krishnan V, MacDougald O . Roles for miRNA-378/378* in adipocyte gene expression and lipogenesis. Am J Physiol Endocrinol Metab. 2010; 299(2):E198-206. PMC: 2928515. DOI: 10.1152/ajpendo.00179.2010. View

16.

Sodir N, Swigart L, Karnezis A, Hanahan D, Evan G, Soucek L . Endogenous Myc maintains the tumor microenvironment. Genes Dev. 2011; 25(9):907-16. PMC: 3084025. DOI: 10.1101/gad.2038411. View

17.

Challagundla K, Sun X, Zhang X, DeVine T, Zhang Q, Sears R . Ribosomal protein L11 recruits miR-24/miRISC to repress c-Myc expression in response to ribosomal stress. Mol Cell Biol. 2011; 31(19):4007-21. PMC: 3187350. DOI: 10.1128/MCB.05810-11. View

18.

Liao J, Lu H . Autoregulatory suppression of c-Myc by miR-185-3p. J Biol Chem. 2011; 286(39):33901-9. PMC: 3190790. DOI: 10.1074/jbc.M111.262030. View

19.

Frenzel A, Zirath H, Vita M, Albihn A, Henriksson M . Identification of cytotoxic drugs that selectively target tumor cells with MYC overexpression. PLoS One. 2011; 6(11):e27988. PMC: 3223192. DOI: 10.1371/journal.pone.0027988. View

20.

Lo D, Dai M, Sun X, Zeng S, Lu H . Ubiquitin- and MDM2 E3 ligase-independent proteasomal turnover of nucleostemin in response to GTP depletion. J Biol Chem. 2012; 287(13):10013-10020. PMC: 3323031. DOI: 10.1074/jbc.M111.335141. View