Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation

Title:
Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation
Authors:
Kapur, Arvinder; Felder, Mildred; Fass, Lucas; Kaur, Justanjot; Czarnecki, Austin; Rathi, Kavya; Zeng, San; Osowski, Kathryn Kalady; Howell, Colin; Xiong, May P.; Whelan, Rebecca J. ( 0000-0002-9293-1528 ) ; Patankar, Manish S.
Abstract:
The monoterpenoid, citral, when delivered through PEG-b-PCL nanoparticles inhibits in vivo growth of 4T1 breast tumors. Here, we show that citral inhibits proliferation of multiple human cancer cell lines. In p53 expressing ECC-1 and OVCAR-3 but not in p53-deficient SKOV-3 cells, citral induces G1/S cell cycle arrest and apoptosis as determined by Annexin V staining and increased cleaved caspase3 and Bax and decreased Bcl-2. In SKOV-3 cells, citral induces the ER stress markers CHOP, GADD45, EDEM, ATF4, Hsp90, ATG5, and phospho-eIF2 alpha. The molecular chaperone 4-phenylbutyric acid attenuates citral activity in SKOV-3 but not in ECC-1 and OVCAR-3 cells. In p53-expressing cells, citral increases phosphorylation of serine-15 of p53. Activation of p53 increases Bax, PUMA, and NOXA expression. Inhibition of p53 by pifithrin-alpha, attenuates citral-mediated apoptosis. Citral increases intracellular oxygen radicals and this leads to activation of p53. Inhibition of glutathione synthesis by L-buthionine sulfoxamine increases potency of citral. Pretreatment with N-acetylcysteine decreases phosphorylation of p53 in citral-treated ECC-1 and OVCAR-3. These results define a p53-dependent, and in the absence of p53, ER stress-dependent mode of action of citral. This study indicates that citral in PEG-b-PCL nanoparticle formulation should be considered for treatment of breast and other tumors.
Citation:
Kapur, A., M. Felder, L. Fass, et al. 2016. "Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation." Scientific Reports 6: 27530.
Publisher:
Nature Publishing Group
DATE ISSUED:
2016-10-28
Department:
Chemistry and Biochemistry
Type:
Article
PUBLISHED VERSION:
10.1038/srep27530
PERMANENT LINK:
http://hdl.handle.net/11282/620192

Full metadata record

DC FieldValue Language
dc.contributor.authorKapur, Arvinderen
dc.contributor.authorFelder, Mildreden
dc.contributor.authorFass, Lucasen
dc.contributor.authorKaur, Justanjoten
dc.contributor.authorCzarnecki, Austinen
dc.contributor.authorRathi, Kavyaen
dc.contributor.authorZeng, Sanen
dc.contributor.authorOsowski, Kathryn Kaladyen
dc.contributor.authorHowell, Colinen
dc.contributor.authorXiong, May P.en
dc.contributor.authorWhelan, Rebecca J.en
dc.contributor.authorPatankar, Manish S.en
dc.date.accessioned2016-10-28T13:56:59Z-
dc.date.available2016-10-28T13:56:59Z-
dc.date.issued2016-10-28-
dc.identifier.citationKapur, A., M. Felder, L. Fass, et al. 2016. "Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation." Scientific Reports 6: 27530.en
dc.identifier.issn2045-2322-
dc.identifier.urihttp://hdl.handle.net/11282/620192-
dc.description.abstractThe monoterpenoid, citral, when delivered through PEG-b-PCL nanoparticles inhibits in vivo growth of 4T1 breast tumors. Here, we show that citral inhibits proliferation of multiple human cancer cell lines. In p53 expressing ECC-1 and OVCAR-3 but not in p53-deficient SKOV-3 cells, citral induces G1/S cell cycle arrest and apoptosis as determined by Annexin V staining and increased cleaved caspase3 and Bax and decreased Bcl-2. In SKOV-3 cells, citral induces the ER stress markers CHOP, GADD45, EDEM, ATF4, Hsp90, ATG5, and phospho-eIF2 alpha. The molecular chaperone 4-phenylbutyric acid attenuates citral activity in SKOV-3 but not in ECC-1 and OVCAR-3 cells. In p53-expressing cells, citral increases phosphorylation of serine-15 of p53. Activation of p53 increases Bax, PUMA, and NOXA expression. Inhibition of p53 by pifithrin-alpha, attenuates citral-mediated apoptosis. Citral increases intracellular oxygen radicals and this leads to activation of p53. Inhibition of glutathione synthesis by L-buthionine sulfoxamine increases potency of citral. Pretreatment with N-acetylcysteine decreases phosphorylation of p53 in citral-treated ECC-1 and OVCAR-3. These results define a p53-dependent, and in the absence of p53, ER stress-dependent mode of action of citral. This study indicates that citral in PEG-b-PCL nanoparticle formulation should be considered for treatment of breast and other tumors.en
dc.language.isoen_USen
dc.publisherNature Publishing Groupen
dc.identifier.doi10.1038/srep27530-
dc.subject.departmentChemistry and Biochemistryen_US
dc.titleModulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferationen_US
dc.typeArticleen
dc.identifier.journalScientific Reportsen
dc.subject.keywordTumor-suppressor P53en_US
dc.subject.keywordIn-vitroen_US
dc.subject.keywordPharmacological strategyen_US
dc.subject.keywordChemical chaperonesen_US
dc.subject.keywordBax geneen_US
dc.subject.keywordGlutathioneen_US
dc.subject.keywordCarcinomaen_US
dc.subject.keywordMiceen_US
dc.subject.keywordTraffickingen_US
dc.subject.keywordMetabolismen_US
dc.identifier.volume6en_US
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