Roles of nitric oxide on cancer stemness and metastasis in lung cancer cells

Chatchai Chaotham

aDepartment of Pharmacology and Physiology,Faculty of Pharmaceutical Sciences,Chulalongkorn University, Bangkok 10330,Thailand

bCell-Based Drug and Health Product Development Research Unit,Faculty of Pharmaceutical Sciences, Chulalongkorn University,Bangkok 10330,Thailand

cDepartment of Biochemistry and Microbiology,Faculty of Pharmaceutical Sciences,Chulalongkorn University, Bangkok 10330,Thailand

Roles of nitric oxide on cancer stemness and metastasis in lung cancer cells

Pithi Chanvorachotea,b,*,Varisa Pongrakhananona,b, Chatchai Chaothamb,c

aDepartment of Pharmacology and Physiology,Faculty of Pharmaceutical Sciences,Chulalongkorn University, Bangkok 10330,Thailand

bCell-Based Drug and Health Product Development Research Unit,Faculty of Pharmaceutical Sciences, Chulalongkorn University,Bangkok 10330,Thailand

cDepartment of Biochemistry and Microbiology,Faculty of Pharmaceutical Sciences,Chulalongkorn University, Bangkok 10330,Thailand

A R T I C L E I N F O

Article history:

Available online 23 November 2015

Cancer stemness

Metastasis

Lung cancer cells

The cancer microenvironment has been reported to have a signifcant impact on cancer cells in many ways.Indeed,in such an active environment,cell signaling molecules as well as mediators including proinfammatory cytokines and reactive species are found to be intensifed.Among them,the concentrations of nitric oxide(NO),a reactive nitrogen species synthesized by many cells,such as endothelial,immune,and tumor cells,are found to be dramatically increased in lung cancer environments[1].Additionally,clinical observation has shown that NO levels in the lungs of lung cancer patients were increased in comparison to those of normal subjects[2].Together,these studies strongly support the role of NO in tumorigenesis and metastasis,although the underlying mechanisms remain obscure.

Increasing evidence has indicated the role of cancer stem cells(CSCs)in cancer aggressiveness,chemoresistance,and relapse;they are being considered as the underlying causes of the high mortality rate of cancer and have been a target of new cancer therapeutic strategies[3].We hypothesize that NO may mediate its procarcinogenic effects through CSCs because of their importance in cancer aggressiveness described above. Here we found that NO plays an important role in the regulation of CSC-like phenotypes of human lung cancer cells.NO induces an upregulation of CSC markers,CD133 and ALDH1A1, along with the increase in anoikis resistance,migration,invasion,and colony-formation activities(Fig.1A–C).Such induction of the aggressive CSC-like behaviors is dependent on Cav-1 expression;however,the expression of CSC markersis independent or inversely dependent on the Cav-1 expression.Because increased NO production has been associated with several human cancers,NO may be one of the key regulators of CSCs and metastasis.This novel fnding on the role of NO and Cav-1 in CSC regulation may have important implications in cancer chemotherapy and prevention.

Fig.1–DPTA,a nitric oxide donor,mediates cancer stem cell-like phenotypes,including(A)anchorage-independent growth,(B)cell migration,and(C)stem cell markers.

Acknowledgement

The authors acknowledge the fnancial support received from Thailand Research Fund(RSA5780043).

R E F E R E N C E S

[1]Keibel A,Singh V,Sharma MC.Infammation, microenvironment,and the immune system in cancer progression.Curr Pharm Des 2009;15:1949–1955.

[2]Esme H,Cemek M,Sezer M,et al.High levels of oxidative stress in patients with advanced lung cancer.Respirology 2008;13:112–116.

[3]O’Connor ML,Xiang D,Shigdar S,et al.Cancer stem cells:a contentious hypothesis now moving forward.Cancer Lett 2014;344:180–187.

*E-mail address:pithi_chan@yahoo.com.

Peer review under responsibility of Shenyang Pharmaceutical University.

http://dx.doi.org/10.1016/j.ajps.2015.10.017

1818-0876/©2016 Production and hosting by Elsevier B.V.on behalf of Shenyang Pharmaceutical University.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).