A small molecule drug promoting miRNA processing induces
alternative splicing of MdmX transcript and rescues p53
activity in human cancer cells overexpressing MdmX protein

J 2017

A small molecule drug promoting miRNA processing induces alternative splicing of MdmX transcript and rescues p53 activity in human cancer cells overexpressing MdmX protein

VALIANATOS, Georgios, Barbora VALČÍKOVÁ, Kateřina GROWKOVÁ, Amandine VERLANDE, Jitka VAŇÁČKOVÁ et. al.

Basic information

Original name

A small molecule drug promoting miRNA processing induces alternative splicing of MdmX transcript and rescues p53 activity in human cancer cells overexpressing MdmX protein

Authors

VALIANATOS, Georgios (300 Greece, belonging to the institution), Barbora VALČÍKOVÁ (203 Czech Republic, belonging to the institution), Kateřina GROWKOVÁ (203 Czech Republic, belonging to the institution), Amandine VERLANDE (250 France, belonging to the institution), Jitka VAŇÁČKOVÁ (203 Czech Republic, belonging to the institution), Lenka RADOVÁ (203 Czech Republic, belonging to the institution), Monika ŠTĚTKOVÁ (203 Czech Republic, belonging to the institution), Michaela VYHŇÁKOVÁ (203 Czech Republic, belonging to the institution), Ondřej SLABÝ (203 Czech Republic, belonging to the institution) and Stjepan ULDRIJAN (203 Czech Republic, guarantor, belonging to the institution)

Edition

Plos one, San Francisco, Public Library of Science, 2017, 1932-6203

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10600 1.6 Biological sciences

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 2.766

RIV identification code

RIV/00216224:14110/17:00095215

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1371/journal.pone.0185801

UT WoS

000412131900055

Keywords in English

MdmX transcript; MdmX protein; human cancer

Abstract

V originále

MdmX overexpression contributes to the development of cancer by inhibiting tumor suppressor p53. A switch in the alternative splicing of MdmX transcript, leading to the inclusion of exon 6, has been identified as the primary mechanism responsible for increased MdmX protein levels in human cancers, including melanoma. However, there are no approved drugs, which could translate these new findings into clinical applications. We analyzed the anti-melanoma activity of enoxacin, a fluoroquinolone antibiotic inhibiting the growth of some human cancers in vitro and in vivo by promoting miRNA maturation. We found that enoxacin inhibited the growth and viability of human melanoma cell lines much stronger than a structurally related fluoroquinolone ofloxacin, which only weakly modulates miRNA processing. A microarray analysis identified a set of miRNAs significantly dysregulated in enoxacin-treated A375 melanoma cells. They had the potential to target multiple signaling pathways required for cancer cell growth, among them the RNA splicing. Recent studies showed that interfering with cellular splicing machinery can result in MdmX downregulation in cancer cells. We, therefore, hypothesized that enoxacin could, by modulating miRNAs targeting splicing machinery, activate p53 in melanoma cells overexpressing MdmX. We found that enoxacin and ciprofloxacin, a related fluoroquinolone capable of promoting microRNA processing, but not ofloxacin, strongly activated wild type p53-dependent transcription in A375 melanoma without causing significant DNA damage. On the molecular level, the drugs promoted MdmX exon 6 skipping, leading to a dose-dependent downregulation of MdmX. Not only in melanoma, but also in MCF7 breast carcinoma and A2780 ovarian carcinoma cells overexpressing MdmX. Together, our results suggest that some clinically approved fluoroquinolones could potentially be repurposed as activators of p53 tumor suppressor in cancers overexpressing MdmX oncoprotein and that p53 activation might contribute to the previously reported activity of enoxacin towards human cancer cells.

Links

EE2.3.30.0009, research and development project

Name: Zaměstnáním čerstvých absolventů doktorského studia k vědecké excelenci

GA14-12166S, research and development project

Name: Regulace dráhy nádorového supresoru p53 novými vazebnými partnery onkogenů Mdm2 a Mdm4

Investor: Czech Science Foundation

MUNI/A/0810/2016, interní kód MU

Name: Molekulární a buněčná biologie

Investor: Masaryk University, Category A

Citovat

VALIANATOS, Georgios, Barbora VALČÍKOVÁ, Kateřina GROWKOVÁ, Amandine VERLANDE, Jitka VAŇÁČKOVÁ, Lenka RADOVÁ, Monika ŠTĚTKOVÁ, Michaela VYHŇÁKOVÁ, Ondřej SLABÝ and Stjepan ULDRIJAN. A small molecule drug promoting miRNA processing induces alternative splicing of MdmX transcript and rescues p53 activity in human cancer cells overexpressing MdmX protein. Plos one. San Francisco: Public Library of Science, 2017, vol. 12, No 10, p. 1-18. ISSN 1932-6203. Available from: https://dx.doi.org/10.1371/journal.pone.0185801.

@article{1397187,
   author = {Valianatos, Georgios and Valčíková, Barbora and Growková, Kateřina and Verlande, Amandine and Vaňáčková, Jitka and Radová, Lenka and Štětková, Monika and Vyhňáková, Michaela and Slabý, Ondřej and Uldrijan, Stjepan},
   article_location = {San Francisco},
   article_number = {10},
   doi = {http://dx.doi.org/10.1371/journal.pone.0185801},
   keywords = {MdmX transcript; MdmX protein; human cancer},
   language = {eng},
   issn = {1932-6203},
   journal = {Plos one},
   title = {A small molecule drug promoting miRNA processing induces alternative splicing of MdmX transcript and rescues p53 activity in human cancer cells overexpressing MdmX protein},
   volume = {12},
   year = {2017}
}

TY  - JOUR
ID  - 1397187
AU  - Valianatos, Georgios - Valčíková, Barbora - Growková, Kateřina - Verlande, Amandine - Vaňáčková, Jitka - Radová, Lenka - Štětková, Monika - Vyhňáková, Michaela - Slabý, Ondřej - Uldrijan, Stjepan
PY  - 2017
TI  - A small molecule drug promoting miRNA processing induces alternative splicing of MdmX transcript and rescues p53 activity in human cancer cells overexpressing MdmX protein
JF  - Plos one
VL  - 12
IS  - 10
SP  - 1-18
EP  - 1-18
PB  - Public Library of Science
SN  - 19326203
KW  - MdmX transcript
KW  - MdmX protein
KW  - human cancer
N2  - MdmX overexpression contributes to the development of cancer by inhibiting tumor suppressor p53. A switch in the alternative splicing of MdmX transcript, leading to the inclusion of exon 6, has been identified as the primary mechanism responsible for increased MdmX protein levels in human cancers, including melanoma. However, there are no approved drugs, which could translate these new findings into clinical applications. We analyzed the anti-melanoma activity of enoxacin, a fluoroquinolone antibiotic inhibiting the growth of some human cancers in vitro and in vivo by promoting miRNA maturation. We found that enoxacin inhibited the growth and viability of human melanoma cell lines much stronger than a structurally related fluoroquinolone ofloxacin, which only weakly modulates miRNA processing. A microarray analysis identified a set of miRNAs significantly dysregulated in enoxacin-treated A375 melanoma cells. They had the potential to target multiple signaling pathways required for cancer cell growth, among them the RNA splicing. Recent studies showed that interfering with cellular splicing machinery can result in MdmX downregulation in cancer cells. We, therefore, hypothesized that enoxacin could, by modulating miRNAs targeting splicing machinery, activate p53 in melanoma cells overexpressing MdmX. We found that enoxacin and ciprofloxacin, a related fluoroquinolone capable of promoting microRNA processing, but not ofloxacin, strongly activated wild type p53-dependent transcription in A375 melanoma without causing significant DNA damage. On the molecular level, the drugs promoted MdmX exon 6 skipping, leading to a dose-dependent downregulation of MdmX. Not only in melanoma, but also in MCF7 breast carcinoma and A2780 ovarian carcinoma cells overexpressing MdmX. Together, our results suggest that some clinically approved fluoroquinolones could potentially be repurposed as activators of p53 tumor suppressor in cancers overexpressing MdmX oncoprotein and that p53 activation might contribute to the previously reported activity of enoxacin towards human cancer cells.
ER  -

VALIANATOS, Georgios, Barbora VALČÍKOVÁ, Kateřina GROWKOVÁ, Amandine VERLANDE, Jitka VAŇÁČKOVÁ, Lenka RADOVÁ, Monika ŠTĚTKOVÁ, Michaela VYHŇÁKOVÁ, Ondřej SLABÝ and Stjepan ULDRIJAN. A small molecule drug promoting miRNA processing induces alternative splicing of MdmX transcript and rescues p53 activity in human cancer cells overexpressing MdmX protein. \textit{Plos one}. San Francisco: Public Library of Science, 2017, vol.~12, No~10, p.~1-18. ISSN~1932-6203. Available from: https://dx.doi.org/10.1371/journal.pone.0185801.

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