BIRC6 Modulates the Protein Stability of Axin to Regulate the Growth, Stemness, and Resistance of Renal Cancer Cells Via the β-Catenin Pathway

Overview

Journal ACS Omega

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Feb 26

PMID 38405482

Authors

Kaihua Zhong

Xiaohong Wang

Heyuan Zhang

Nanhui Chen

Yang Mai

Sipin Dai

Lawei Yang

Dong Chen

Weifeng Zhong

Affiliations

Soon will be listed here.

Abstract

The mechanism underlying the development of renal cell carcinoma (RCC) remains unclear, and effective prevention and therapeutic measures are lacking. BIRC6, a protein inhibitor of apoptosis, has attracted great interest. Our data indicated that overexpression of BIRC6 elevated cell growth, colony formation, migration, and invasion of cultured RCC cells, while siRNA knockdown of BIRC6 suppressed these processes. Additionally, BIRC6 was highly expressed in RCC clinical samples along with a downregulated level of Axin. Immunoprecipitation assays found that BIRC6 interacted with Axin and the two proteins colocalized within the cytoplasm of RCC cells. Overexpression of BIRC6 promoted the ubiquitination modification of Axin, while genetic knockdown of BIRC6 suppressed it. Furthermore, overexpression of BIRC6 significantly promoted the turnover of Axin, suggesting BIRC6's inhibitory effect on Axin protein stability. BIRC6 was also upregulated in cancer stem-like cells of RCC and increased the drug resistance of RCC cells against sunitinib. Western blotting assays showed that the overexpression of BIRC6 upregulated CXCR4 protein expression and activated the β-catenin pathway. Two cell lines were then constructed with BIRC6 overexpressed by lentiviruses. Pharmacological administration of a Wnt/β-catenin inhibitor, XAV-939, or genetic knockdown of β-catenin inhibited cell growth, tumor sphere formation, colony formation, migration, and invasion of BIRC6-overexpressed cells. administration of XAV-939 markedly suppressed the tumorigenesis of BIRC6-overexpressed RCC cells in nude mice. In conclusion, we propose that BIRC6 activates the β-catenin signaling pathway via mediating the ubiquitination and degradation of Axin, promoting the growth, stemness, and drug resistance of RCC cells. This project aims to elucidate the role of BIRC6 as a potential therapeutic target and provide new insights into the clinical treatment of RCC.

References

Pan B, Zhong W, Deng Z, Lai C, Chu J, Jiao G . Inhibition of prostate cancer growth by solanine requires the suppression of cell cycle proteins and the activation of ROS/P38 signaling pathway. Cancer Med. 2016; 5(11):3214-3222. PMC: 5119977. DOI: 10.1002/cam4.916. View

Liu T, Xue R, Huang X, Zhang D, Dong L, Wu H . Proteomic profiling of hepatitis B virus-related hepatocellular carcinoma with magnetic bead-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Acta Biochim Biophys Sin (Shanghai). 2011; 43(7):542-50. DOI: 10.1093/abbs/gmr044. View

Tang W, Xue R, Weng S, Wu J, Fang Y, Wang Y . BIRC6 promotes hepatocellular carcinogenesis: interaction of BIRC6 with p53 facilitating p53 degradation. Int J Cancer. 2014; 136(6):E475-87. DOI: 10.1002/ijc.29194. View

Ciccarese C, Strusi A, Arduini D, Russo P, Palermo G, Foschi N . Post nephrectomy management of localized renal cell carcinoma. From risk stratification to therapeutic evidence in an evolving clinical scenario. Cancer Treat Rev. 2023; 115:102528. DOI: 10.1016/j.ctrv.2023.102528. View

Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A . Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J. 1998; 17(5):1371-84. PMC: 1170485. DOI: 10.1093/emboj/17.5.1371. View

Ren J, Shi M, Liu R, Yang Q, Johnson T, Skarnes W . The Birc6 (Bruce) gene regulates p53 and the mitochondrial pathway of apoptosis and is essential for mouse embryonic development. Proc Natl Acad Sci U S A. 2005; 102(3):565-70. PMC: 543482. DOI: 10.1073/pnas.0408744102. View

Sung K, Choi J, Kyeong Hwang Y, Lee S, Kim H, Lee S . Overexpression of Apollon, an antiapoptotic protein, is associated with poor prognosis in childhood de novo acute myeloid leukemia. Clin Cancer Res. 2007; 13(17):5109-14. DOI: 10.1158/1078-0432.CCR-07-0693. View

Ge C, Vilfranc C, Che L, Pandita R, Hambarde S, Andreassen P . The BRUCE-ATR Signaling Axis Is Required for Accurate DNA Replication and Suppression of Liver Cancer Development. Hepatology. 2019; 69(6):2608-2622. PMC: 6541504. DOI: 10.1002/hep.30529. View

Duchartre Y, Kim Y, Kahn M . The Wnt signaling pathway in cancer. Crit Rev Oncol Hematol. 2016; 99:141-9. PMC: 5853106. DOI: 10.1016/j.critrevonc.2015.12.005. View

10.

Wiechens N, Heinle K, Englmeier L, Schohl A, Fagotto F . Nucleo-cytoplasmic shuttling of Axin, a negative regulator of the Wnt-beta-catenin Pathway. J Biol Chem. 2003; 279(7):5263-7. DOI: 10.1074/jbc.M307253200. View

11.

Zhang Y, Liu S, Mickanin C, Feng Y, Charlat O, Michaud G . RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nat Cell Biol. 2011; 13(5):623-9. DOI: 10.1038/ncb2222. View

12.

Qiu X, Goldberg A . The membrane-associated inhibitor of apoptosis protein, BRUCE/Apollon, antagonizes both the precursor and mature forms of Smac and caspase-9. J Biol Chem. 2004; 280(1):174-82. DOI: 10.1074/jbc.M411430200. View

13.

Bianchini M, Levy E, Zucchini C, Pinski V, Macagno C, De Sanctis P . Comparative study of gene expression by cDNA microarray in human colorectal cancer tissues and normal mucosa. Int J Oncol. 2006; 29(1):83-94. View

14.

Hsu R, Ho J, Cha T, Yu D, Wu C, Huang W . WNT10A plays an oncogenic role in renal cell carcinoma by activating WNT/β-catenin pathway. PLoS One. 2012; 7(10):e47649. PMC: 3477117. DOI: 10.1371/journal.pone.0047649. View

15.

Corro C, Moch H . Biomarker discovery for renal cancer stem cells. J Pathol Clin Res. 2018; 4(1):3-18. PMC: 5783955. DOI: 10.1002/cjp2.91. View

16.

Liang Z, Lu L, Mao J, Li X, Qian H, Xu W . Curcumin reversed chronic tobacco smoke exposure induced urocystic EMT and acquisition of cancer stem cells properties via Wnt/β-catenin. Cell Death Dis. 2017; 8(10):e3066. PMC: 5680574. DOI: 10.1038/cddis.2017.452. View

17.

Saleem M, Qadir M, Perveen N, Saleem U, Irshad T, Ahmad B . Inhibitors of apoptotic proteins: new targets for anticancer therapy. Chem Biol Drug Des. 2013; 82(3):243-51. DOI: 10.1111/cbdd.12176. View

18.

Kruck S, Eyrich C, Scharpf M, Sievert K, Fend F, Stenzl A . Impact of an altered Wnt1/β-catenin expression on clinicopathology and prognosis in clear cell renal cell carcinoma. Int J Mol Sci. 2013; 14(6):10944-57. PMC: 3709711. DOI: 10.3390/ijms140610944. View

19.

Katoh M . Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review). Int J Oncol. 2017; 51(5):1357-1369. PMC: 5642388. DOI: 10.3892/ijo.2017.4129. View

20.

Lopergolo A, Pennati M, Gandellini P, Orlotti N, Poma P, Daidone M . Apollon gene silencing induces apoptosis in breast cancer cells through p53 stabilisation and caspase-3 activation. Br J Cancer. 2009; 100(5):739-46. PMC: 2653776. DOI: 10.1038/sj.bjc.6604927. View