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

TitleLY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cells
Authors
KeywordsAKT
AMPK
LY294002
Metformin
MTOR
Ovarian cancer
Issue Date2012
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.ijgc.net/
Citation
International Journal of Gynecological Cancer, 2012, v. 22 n. 1, p. 15-22 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/143365
ISSN
2014 Impact Factor: 1.958
2014 SCImago Journal Rankings: 0.750
ISI Accession Number ID
Funding AgencyGrant Number
Wong Check She Charitable Foundation
Funding Information:

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

References

 

DC FieldValueLanguage
dc.contributor.authorLi, Cen_HK
dc.contributor.authorLiu, VWSen_HK
dc.contributor.authorChan, DWen_HK
dc.contributor.authorYao, KMen_HK
dc.contributor.authorNgan, HYSen_HK
dc.date.accessioned2011-11-24T10:03:25Z-
dc.date.available2011-11-24T10:03:25Z-
dc.date.issued2012en_HK
dc.identifier.citationInternational Journal of Gynecological Cancer, 2012, v. 22 n. 1, p. 15-22en_HK
dc.identifier.issn1048-891Xen_HK
dc.identifier.urihttp://hdl.handle.net/10722/143365-
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.en_HK
dc.languageengen_US
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.ijgc.net/en_HK
dc.relation.ispartofInternational Journal of Gynecological Canceren_HK
dc.rightsThe definitive version is available at www.blackwell-synergy.comen_US
dc.subjectAKTen_HK
dc.subjectAMPKen_HK
dc.subjectLY294002en_HK
dc.subjectMetforminen_HK
dc.subjectMTORen_HK
dc.subjectOvarian canceren_HK
dc.titleLY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cellsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1048-891X&volume=&spage=&epage=&date=2011&atitle=LY294002+and+Metformin+Cooperatively+Enhance+the+Inhibition+of+Growth+and+the+Induction+of+Apoptosis+of+Ovarian+Cancer+Cellsen_US
dc.identifier.emailLiu, VWS: vwsliu@hkusua.hku.hken_HK
dc.identifier.emailYao, KM: kmyao@hku.hken_HK
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hken_HK
dc.identifier.authorityLiu, VWS=rp00341en_HK
dc.identifier.authorityYao, KM=rp00344en_HK
dc.identifier.authorityNgan, HYS=rp00346en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1097/IGC.0b013e3182322834en_HK
dc.identifier.pmid22080879-
dc.identifier.scopuseid_2-s2.0-84863229883en_HK
dc.identifier.hkuros197744en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84863229883&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume22en_HK
dc.identifier.issue1en_HK
dc.identifier.spage15en_HK
dc.identifier.epage22en_HK
dc.identifier.isiWOS:000298628800005-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLi, C=55277398900en_HK
dc.identifier.scopusauthoridLiu, VWS=7006405113en_HK
dc.identifier.scopusauthoridChan, DW=55276366100en_HK
dc.identifier.scopusauthoridYao, KM=7403234578en_HK
dc.identifier.scopusauthoridNgan, HYS=34571944100en_HK

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