Activin B Antagonizes RhoA Signaling to Stimulate Mesenchymal Morphology and Invasiveness of Clear Cell Renal Cell Carcinomas

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Oct 25

PMID 25343250

Citations 10

Authors

Ingrid Wacker

Jurgen Behrens

Affiliations

Soon will be listed here.

Abstract

Activin B belongs to the TGFβ family of growth factors and is upregulated in clear cell renal cell carcinoma cells by hypoxia inducible factors. Expression of Activin B is required for tumor growth in vivo and tumor cell invasion in vitro. Here we show that activation of RhoA signaling counteracts Activin B mediated disassembly of actin stress fibers, mesenchymal cell morphology and invasiveness, whereas inhibition of RhoA rescues these effects in Activin B knockdown cells. Conversely, Activin B inhibits RhoA signaling suggesting that there is an antagonistic connection between both pathways. In addition we found that Rac1 plays an opposite role to RhoA, i.e. activation of Rac1 initiates loss of actin stress fibers, promotes a mesenchymal cell morphology and induces invasion in Activin B knockown cells, whereas inhibition of Rac1 abolishes these Activin B effects. Collectively, our data provide evidence that reduction of RhoA signaling by Activin B together with persistent Rac1 activity is a prerequisite for inducing an invasive phenotype in clear cell renal cell carcinoma.

Citing Articles

Inhibin subunit beta B (INHBB): an emerging role in tumor progression.

Liu Y, Zhou Q, Zou G, Zhang W J Physiol Biochem. 2024; 80(4):775-793.

PMID: 39183219 DOI: 10.1007/s13105-024-01041-y.

Study on the value of Inhibin B in the diagnosis of nasopharyngeal carcinoma and its correlation with traditional Chinese medicine syndromes: An observational study.

Ma N, Deng X, Liu Q, Xu F, Guo Q, Yan K Medicine (Baltimore). 2024; 103(23):e38416.

PMID: 38847724 PMC: 11155563. DOI: 10.1097/MD.0000000000038416.

A Machine Learning Computational Framework Develops a Multiple Programmed Cell Death Index for Improving Clinical Outcomes in Bladder Cancer.

Li C, Qin W, Hu J, Lin J, Mao Y Biochem Genet. 2024; 62(6):4710-4737.

PMID: 38353892 DOI: 10.1007/s10528-024-10683-y.

A-kinase interacting protein 1 regulates the cell proliferation, invasion, migration and angiogenesis of clear cell renal cell carcinoma cells and affects the ERK/c-Myc signaling pathway by binding to Rac1.

Zhang Y, Zhang H, Han Z, Wang X, Li X, Yuan P Exp Ther Med. 2022; 24(3):558.

PMID: 35978938 PMC: 9366277. DOI: 10.3892/etm.2022.11489.

INHBB Is a Novel Prognostic Biomarker Associated with Cancer-Promoting Pathways in Colorectal Cancer.

Yuan J, Xie A, Cao Q, Li X, Chen J Biomed Res Int. 2020; 2020:6909672.

PMID: 33083477 PMC: 7563060. DOI: 10.1155/2020/6909672.

References

Pawlak G, Helfman D . Post-transcriptional down-regulation of ROCKI/Rho-kinase through an MEK-dependent pathway leads to cytoskeleton disruption in Ras-transformed fibroblasts. Mol Biol Cell. 2002; 13(1):336-47. PMC: 65092. DOI: 10.1091/mbc.01-06-0302. View

Semenza G . Hypoxia-inducible factor 1 and cancer pathogenesis. IUBMB Life. 2008; 60(9):591-7. DOI: 10.1002/iub.93. View

Brown C, Woodruff T, Matzuk M . Insertion of Inhbb into the Inhba locus rescues the Inhba-null phenotype and reveals new activin functions. Nat Genet. 2000; 25(4):453-7. DOI: 10.1038/78161. View

Safina A, Varga A, Bianchi A, Zheng Q, Kunnev D, Liang P . Ras alters epithelial-mesenchymal transition in response to TGFbeta by reducing actin fibers and cell-matrix adhesion. Cell Cycle. 2009; 8(2):284-98. DOI: 10.4161/cc.8.2.7590. View

Shen C, Kaelin Jr W . The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol. 2012; 23(1):18-25. PMC: 3663044. DOI: 10.1016/j.semcancer.2012.06.001. View

Wolf K, Mazo I, Leung H, Engelke K, von Andrian U, Deryugina E . Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J Cell Biol. 2003; 160(2):267-77. PMC: 2172637. DOI: 10.1083/jcb.200209006. View

Nimnual A, Taylor L, Bar-Sagi D . Redox-dependent downregulation of Rho by Rac. Nat Cell Biol. 2003; 5(3):236-41. DOI: 10.1038/ncb938. View

Lehmann K, Janda E, Pierreux C, Rytomaa M, Schulze A, McMahon M . Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev. 2000; 14(20):2610-22. PMC: 316988. DOI: 10.1101/gad.181700. View

Yang S, Kim H . ROCK inhibition activates MCF-7 cells. PLoS One. 2014; 9(2):e88489. PMC: 3921164. DOI: 10.1371/journal.pone.0088489. View

10.

Brummelkamp T, Bernards R, Agami R . A system for stable expression of short interfering RNAs in mammalian cells. Science. 2002; 296(5567):550-3. DOI: 10.1126/science.1068999. View

11.

Janke J, Schluter K, Jandrig B, Theile M, Kolble K, Arnold W . Suppression of tumorigenicity in breast cancer cells by the microfilament protein profilin 1. J Exp Med. 2000; 191(10):1675-86. PMC: 2193149. DOI: 10.1084/jem.191.10.1675. View

12.

Heasman S, Ridley A . Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008; 9(9):690-701. DOI: 10.1038/nrm2476. View

13.

Sadok A, Marshall C . Rho GTPases: masters of cell migration. Small GTPases. 2014; 5:e29710. PMC: 4107589. DOI: 10.4161/sgtp.29710. View

14.

Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T . Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem. 1996; 271(34):20246-9. DOI: 10.1074/jbc.271.34.20246. View

15.

Krieg M, Haas R, Brauch H, Acker T, Flamme I, Plate K . Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene. 2000; 19(48):5435-43. DOI: 10.1038/sj.onc.1203938. View

16.

Leto G, Incorvaia L, Badalamenti G, Tumminello F, Gebbia N, Flandina C . Activin A circulating levels in patients with bone metastasis from breast or prostate cancer. Clin Exp Metastasis. 2006; 23(2):117-22. DOI: 10.1007/s10585-006-9010-5. View

17.

Mukerji S, Rainey R, Rhodes J, Hall A . Delayed activin A administration attenuates tissue death after transient focal cerebral ischemia and is associated with decreased stress-responsive kinase activation. J Neurochem. 2009; 111(5):1138-48. PMC: 2792943. DOI: 10.1111/j.1471-4159.2009.06406.x. View

18.

Wacker I, Sachs M, Knaup K, Wiesener M, Weiske J, Huber O . Key role for activin B in cellular transformation after loss of the von Hippel-Lindau tumor suppressor. Mol Cell Biol. 2009; 29(7):1707-18. PMC: 2655617. DOI: 10.1128/MCB.01184-07. View

19.

Antsiferova M, Huber M, Meyer M, Piwko-Czuchra A, Ramadan T, MacLeod A . Activin enhances skin tumourigenesis and malignant progression by inducing a pro-tumourigenic immune cell response. Nat Commun. 2011; 2:576. PMC: 3247817. DOI: 10.1038/ncomms1585. View

20.

Ageta H, Murayama A, Migishima R, Kida S, Tsuchida K, Yokoyama M . Activin in the brain modulates anxiety-related behavior and adult neurogenesis. PLoS One. 2008; 3(4):e1869. PMC: 2270335. DOI: 10.1371/journal.pone.0001869. View