Article: LY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cells

File Download Links for fulltext
(May Require Subscription)
Supplementary

  • Basic View
  • Metadata View
  • XML View
TitleLY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cells
AuthorsLi, C1
Liu, VWS1
Chan, DW1
Yao, KM1
Ngan, HYS1
KeywordsAKT
AMPK
LY294002
Metformin
MTOR
Ovarian cancer
Issue Date2012
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.ijgc.net/
CitationInternational Journal of Gynecological Cancer, 2012, v. 22 n. 1, p. 15-22 [How to Cite?]
DOI: http://dx.doi.org/10.1097/IGC.0b013e3182322834
AbstractBackground: The phosphoinositide 3 kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is frequently aberrantly activated in ovarian cancer and confers the chemoresistant phenotype of ovarian cancer cells. LY294002 (PI3K inhibitor) and metformin (5′-adenosine monophosphate [AMP]-activated protein kinase [AMPK] activator) are 2 drugs that were known to inhibit mTOR expression through the AKT-dependent and AKT-independent pathways, respectively. In this study, we explored the effectiveness of LY294002 and metformin in combination on inhibition of ovarian cancer cell growth. Methods: Western blotting was used to detect the changes of PI3K/AKT/mTOR and AMPK/acetyl-CoA carboxylase (ACC) signaling activities, cell cycle control, and apoptosis. Cell growth was evaluated by cell proliferation, colony formation, and soft agar assays. Flow cytometry was used to study cell cycle distribution and cell death upon drug treatment. Results: Our study showed that LY294002 and metformin in combination could simultaneously enhance the repression of the PI3K/AKT/mTOR pathway and the activation of the AMPK/ACC pathway. The downstream target of AKT and AMPK, mTOR, was cooperatively repressed when the drugs were used together. The cell cycle regulatory factors, p53, p27, and p21, were up-regulated. On the other hand, caspase 3 and poly (ADP-ribose) polymerase activities involved in apoptosis were also activated. Cell growth assays indicated that LY294002 and metformin could effectively inhibit ovarian cancer cell growth. Flow cytometry analysis showed that the treatment of the 2 drugs mentioned above induced cell cycle arrest at G1 phase and increased sub-G1 apoptotic cells. Conclusion: The combinational use of LY294002 and metformin can enhance inhibition of the growth and induction of the apoptosis of ovarian cancer cells. Our results may provide significant insight into the future therapeutic regimens in ovarian cancer. Copyright © 2012 by IGCS and ESGO.
ISSN1048-891X
2011 Impact Factor: 1.646
2011 SCImago Journal Rankings: 0.181
DOIhttp://dx.doi.org/10.1097/IGC.0b013e3182322834
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorLi, C
dc.contributor.authorLiu, VWS
dc.contributor.authorChan, DW
dc.contributor.authorYao, KM
dc.contributor.authorNgan, HYS
dc.date.accessioned2011-11-24T10:03:25Z
dc.date.available2011-11-24T10:03:25Z
dc.date.issued2012
dc.description.abstractBackground: The phosphoinositide 3 kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is frequently aberrantly activated in ovarian cancer and confers the chemoresistant phenotype of ovarian cancer cells. LY294002 (PI3K inhibitor) and metformin (5′-adenosine monophosphate [AMP]-activated protein kinase [AMPK] activator) are 2 drugs that were known to inhibit mTOR expression through the AKT-dependent and AKT-independent pathways, respectively. In this study, we explored the effectiveness of LY294002 and metformin in combination on inhibition of ovarian cancer cell growth. Methods: Western blotting was used to detect the changes of PI3K/AKT/mTOR and AMPK/acetyl-CoA carboxylase (ACC) signaling activities, cell cycle control, and apoptosis. Cell growth was evaluated by cell proliferation, colony formation, and soft agar assays. Flow cytometry was used to study cell cycle distribution and cell death upon drug treatment. Results: Our study showed that LY294002 and metformin in combination could simultaneously enhance the repression of the PI3K/AKT/mTOR pathway and the activation of the AMPK/ACC pathway. The downstream target of AKT and AMPK, mTOR, was cooperatively repressed when the drugs were used together. The cell cycle regulatory factors, p53, p27, and p21, were up-regulated. On the other hand, caspase 3 and poly (ADP-ribose) polymerase activities involved in apoptosis were also activated. Cell growth assays indicated that LY294002 and metformin could effectively inhibit ovarian cancer cell growth. Flow cytometry analysis showed that the treatment of the 2 drugs mentioned above induced cell cycle arrest at G1 phase and increased sub-G1 apoptotic cells. Conclusion: The combinational use of LY294002 and metformin can enhance inhibition of the growth and induction of the apoptosis of ovarian cancer cells. Our results may provide significant insight into the future therapeutic regimens in ovarian cancer. Copyright © 2012 by IGCS and ESGO.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationInternational Journal of Gynecological Cancer, 2012, v. 22 n. 1, p. 15-22 [How to Cite?]
DOI: http://dx.doi.org/10.1097/IGC.0b013e3182322834
dc.identifier.doihttp://dx.doi.org/10.1097/IGC.0b013e3182322834
dc.identifier.epage22
dc.identifier.hkuros197744
dc.identifier.isiWOS:000298628800005
Funding AgencyGrant Number
Wong Check She Charitable Foundation
Funding Information:

This study was generously supported by the Wong Check She Charitable Foundation.

dc.identifier.issn1048-891X
2011 Impact Factor: 1.646
2011 SCImago Journal Rankings: 0.181
dc.identifier.issue1
dc.identifier.openurl
dc.identifier.pmid22080879
dc.identifier.scopuseid_2-s2.0-84863229883
dc.identifier.spage15
dc.identifier.urihttp://hdl.handle.net/10722/143365
dc.identifier.volume22
dc.languageeng
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.ijgc.net/
dc.publisher.placeUnited States
dc.relation.ispartofInternational Journal of Gynecological Cancer
dc.relation.referencesReferences in Scopus
dc.rightsThe definitive version is available at www.blackwell-synergy.com
dc.subjectAKT
dc.subjectAMPK
dc.subjectLY294002
dc.subjectMetformin
dc.subjectMTOR
dc.subjectOvarian cancer
dc.titleLY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cells
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine