Growth Inhibition Associated with Disruption of the Actin Cytoskeleton by Latrunculin A in Rhabdomyosarcoma Cells

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2020 Sep 8

PMID 32898143

Citations 1

Authors

Julia Wurtemberger

Daria Tchessalova

Carla Regina

Christoph Bauer

Michaela Schneider

Amy J Wagers

Simone Hettmer

Affiliations

Soon will be listed here.

Abstract

Functional genomic screening of KRAS-driven mouse sarcomas was previously employed to identify proliferation-relevant genes. Genes identified included Ubiquitin-conjugating enzyme E2 (Ube2c), Centromere Protein E (Cenpe), Hyaluronan Synthase 2 (Has2), and CAMP Responsive Element Binding Protein 3 Like 2 (Creb3l2). This study examines the expression and chemical inhibition of these candidate genes, identifying variable levels of protein expression and significant contributions to rhabdomyosarcoma (RMS) cell proliferation. Chemical treatment of human and murine RMS cell lines with bortezomib, UA62784, latrunculin A and sorafenib inhibited growth with approximate EC50 concentrations of 15-30nM for bortezomib, 25-80nM for UA62784 and 80-220nM for latrunculin A. The multi-kinase inhibitor sorafenib increased in vitro proliferation of 4 of 6 sarcoma cell lines tested. Latrunculin A was further associated with disruption of the actin cytoskeleton and reduced ERK1/2 phosphorylation. Together, this work advances opportunities for developing therapies to block progression of soft-tissue sarcomas and demonstrates that disruption of the actin cytoskeleton in sarcoma cells by latrunculin A is associated with a reduction in RMS cell growth. (167 words).

Citing Articles

Disturbing cytoskeleton by engineered nanomaterials for enhanced cancer therapeutics.

Xu X, Xu S, Wan J, Wang D, Pang X, Gao Y Bioact Mater. 2023; 29:50-71.

PMID: 37621771 PMC: 10444958. DOI: 10.1016/j.bioactmat.2023.06.016.

References

Hettmer S, Li Z, Billin A, Barr F, Cornelison D, Ehrlich A . Rhabdomyosarcoma: current challenges and their implications for developing therapies. Cold Spring Harb Perspect Med. 2014; 4(11):a025650. PMC: 4208704. DOI: 10.1101/cshperspect.a025650. View

Parham D, Barr F . Classification of rhabdomyosarcoma and its molecular basis. Adv Anat Pathol. 2013; 20(6):387-97. PMC: 6637949. DOI: 10.1097/PAP.0b013e3182a92d0d. View

Yoo J, Robinson R, Lee J . H-ras and K-ras gene mutations in primary human soft tissue sarcoma: concomitant mutations of the ras genes. Mod Pathol. 1999; 12(8):775-80. View

Sperka T, Geissler K, Merkel U, Scholl I, Rubio I, Herrlich P . Activation of Ras requires the ERM-dependent link of actin to the plasma membrane. PLoS One. 2011; 6(11):e27511. PMC: 3221661. DOI: 10.1371/journal.pone.0027511. View

Sheng Z, Li L, Zhu L, Smith T, Demers A, Ross A . A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications. Nat Med. 2010; 16(6):671-7. PMC: 2882506. DOI: 10.1038/nm.2158. View

Shern J, Chen L, Chmielecki J, Wei J, Patidar R, Rosenberg M . Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov. 2014; 4(2):216-31. PMC: 4462130. DOI: 10.1158/2159-8290.CD-13-0639. View

Henderson M, Shaw Y, Wang H, Han H, Hurley L, Flynn G . UA62784, a novel inhibitor of centromere protein E kinesin-like protein. Mol Cancer Ther. 2009; 8(1):36-44. PMC: 2634858. DOI: 10.1158/1535-7163.MCT-08-0789. View

Tcherniuk S, Deshayes S, Sarli V, Divita G, Abrieu A . UA62784 Is a cytotoxic inhibitor of microtubules, not CENP-E. Chem Biol. 2011; 18(5):631-41. DOI: 10.1016/j.chembiol.2011.03.006. View

Houghton P, Morton C, Kolb E, Lock R, Carol H, Reynolds C . Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program. Pediatr Blood Cancer. 2007; 50(1):37-45. DOI: 10.1002/pbc.21214. View

10.

El Sayed K, Khanfar M, Shallal H, Muralidharan A, Awate B, Youssef D . Latrunculin A and its C-17-O-carbamates inhibit prostate tumor cell invasion and HIF-1 activation in breast tumor cells. J Nat Prod. 2008; 71(3):396-402. PMC: 2930178. DOI: 10.1021/np070587w. View

11.

Crago A, Brennan M . Principles in Management of Soft Tissue Sarcoma. Adv Surg. 2015; 49:107-22. PMC: 4574518. DOI: 10.1016/j.yasu.2015.04.002. View

12.

Konishi H, Kikuchi S, Ochiai T, Ikoma H, Kubota T, Ichikawa D . Latrunculin a has a strong anticancer effect in a peritoneal dissemination model of human gastric cancer in mice. Anticancer Res. 2009; 29(6):2091-7. View

13.

Fujiwara I, Zweifel M, Courtemanche N, Pollard T . Latrunculin A Accelerates Actin Filament Depolymerization in Addition to Sequestering Actin Monomers. Curr Biol. 2018; 28(19):3183-3192.e2. PMC: 6179359. DOI: 10.1016/j.cub.2018.07.082. View

14.

Rock K, Grandoch M, Majora M, Krutmann J, Fischer J . Collagen fragments inhibit hyaluronan synthesis in skin fibroblasts in response to ultraviolet B (UVB): new insights into mechanisms of matrix remodeling. J Biol Chem. 2011; 286(20):18268-76. PMC: 3093899. DOI: 10.1074/jbc.M110.201665. View

15.

Bavi P, Uddin S, Ahmed M, Jehan Z, Bu R, Abubaker J . Bortezomib stabilizes mitotic cyclins and prevents cell cycle progression via inhibition of UBE2C in colorectal carcinoma. Am J Pathol. 2011; 178(5):2109-20. PMC: 3081207. DOI: 10.1016/j.ajpath.2011.01.034. View

16.

Gwinn D, Lee A, Briones-Martin-Del-Campo M, Conn C, Simpson D, Scott A . Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase. Cancer Cell. 2018; 33(1):91-107.e6. PMC: 5761662. DOI: 10.1016/j.ccell.2017.12.003. View

17.

Hettmer S, Liu J, Miller C, Lindsay M, Sparks C, Guertin D . Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells. Proc Natl Acad Sci U S A. 2011; 108(50):20002-7. PMC: 3250188. DOI: 10.1073/pnas.1111733108. View

18.

Ayscough K, Stryker J, Pokala N, Sanders M, Crews P, Drubin D . High rates of actin filament turnover in budding yeast and roles for actin in establishment and maintenance of cell polarity revealed using the actin inhibitor latrunculin-A. J Cell Biol. 1997; 137(2):399-416. PMC: 2139767. DOI: 10.1083/jcb.137.2.399. View

19.

Doller A, Badawi A, Schmid T, Brauss T, Pleli T, Heringdorf D . The cytoskeletal inhibitors latrunculin A and blebbistatin exert antitumorigenic properties in human hepatocellular carcinoma cells by interfering with intracellular HuR trafficking. Exp Cell Res. 2014; 330(1):66-80. DOI: 10.1016/j.yexcr.2014.09.010. View

20.

Linch M, Miah A, Thway K, Judson I, Benson C . Systemic treatment of soft-tissue sarcoma-gold standard and novel therapies. Nat Rev Clin Oncol. 2014; 11(4):187-202. DOI: 10.1038/nrclinonc.2014.26. View