ROCK inhibition with Fasudil induces beta-catenin nuclear translocation and inhibits cell migration of MDA-MB 231 human breast cancer cells

Tumor aggressiveness is usually associated with metastasis. MDA-MB 231, a triple-negative breast cancer (TNBC), is an aggressive type of breast cancer and associated with early metastasis. The Rho/ROCK pathway is a key regulator of cell motility involving cytoskeleton regulation through stabilization of actin filaments and stress fiber formation. In this study we show that Fasudil, a ROCK inhibitor, inhibited the migration of MDA-MB 231 and A549 cells, without altering the viability of these cells at the concentration of 10 μM, modified tumor cell morphology, with disorganization of stress fibers and promotes activation of the canonical-Wnt/beta-catenin pathway. Therefore, Fasudil present a promising approach to the prevention of breast cancer metastasis through a different mechanism of action from the well-known one.

[1]  I. Ng,et al.  Rho‐kinase 2 is frequently overexpressed in hepatocellular carcinoma and involved in tumor invasion , 2009, Hepatology.

[2]  B. Alicke,et al.  The Rho kinase inhibitor fasudil inhibits tumor progression in human and rat tumor models , 2006, Molecular Cancer Therapeutics.

[3]  Anne J. Ridley,et al.  ROCKs: multifunctional kinases in cell behaviour , 2003, Nature Reviews Molecular Cell Biology.

[4]  Randall T Moon,et al.  Wnt and calcium signaling: beta-catenin-independent pathways. , 2005, Cell calcium.

[5]  Rebecca L. Siegel Mph,et al.  Cancer statistics, 2016 , 2016 .

[6]  K. Itoh,et al.  Overexpression of small GTP-binding protein RhoA promotes invasion of tumor cells. , 1999, Cancer research.

[7]  Ying Sun,et al.  RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer. , 2012, Cancer research.

[8]  H. Huber,et al.  Nuclear beta-catenin induces an early liver progenitor phenotype in hepatocellular carcinoma and promotes tumor recurrence. , 2010, The American journal of pathology.

[9]  T. Sone,et al.  5-Isoquinolinesulfonamide derivatives. III. Synthesis and vasodilatory activity of 1-(5-isoquinoline-sulfonyl)piperazine derivatives. , 1992, Chemical & pharmaceutical bulletin.

[10]  Zhao-You Tang,et al.  Activation of β-Catenin by Hypoxia in Hepatocellular Carcinoma Contributes to Enhanced Metastatic Potential and Poor Prognosis , 2010, Clinical Cancer Research.

[11]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[12]  Manoel Luis Costa,et al.  Membrane cholesterol depletion reduces breast tumor cell migration by a mechanism that involves non-canonical Wnt signaling and IL-10 secretion , 2016, Translational Medicine Communications.

[13]  J. Liao,et al.  Rho Kinase (ROCK) Inhibitors , 2007, Journal of cardiovascular pharmacology.

[14]  D. Rimm,et al.  β-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas. , 2011, Cancer cell.

[15]  Debra L Winkeljohn.  Triple-negative breast cancer. , 2008, Clinical journal of oncology nursing.

[16]  Randall T. Moon,et al.  Wnt and calcium signaling: β-Catenin-independent pathways , 2005 .

[17]  Sasidhar Vemula,et al.  Distinct roles for ROCK1 and ROCK2 in the regulation of cell detachment , 2013, Cell Death and Disease.

[18]  A. Jemal,et al.  Cancer statistics, 2016 , 2016, CA: a cancer journal for clinicians.

[19]  Hans Clevers,et al.  Actomyosin-Mediated Cellular Tension Drives Increased Tissue Stiffness and β-Catenin Activation to Induce Epidermal Hyperplasia and Tumor Growth. , 2024, Cancer cell.

[20]  N. Tapon,et al.  Rho, Rac and Cdc42 GTPases regulate the organization of the actin cytoskeleton. , 1997, Current opinion in cell biology.

[21]  G. Loirand.  Rho Kinases in Health and Disease: From Basic Science to Translational Research , 2015, Pharmacological Reviews.