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Conference Paper: PIK3R1 loss activates AKT and STAT3 signaling in ovarian cancer

TitlePIK3R1 loss activates AKT and STAT3 signaling in ovarian cancer
Authors
Issue Date2018
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
American Association for Cancer Research Annual Meeting, Chicago, IL, 14-18 April 2018. In Cancer Research, 2018, v. 78 n. 13 Suppl, Abstract no. 3955 How to Cite?
AbstractThe phosphoinositide 3-kinase (PI3K) regulatory subunit p85α is one of the critical gatekeepers of PI3K pathway activation through stabilizing and inhibiting the catalytic subunit p110. p85α is encoded by PIK3R1, which is frequently mutated or deleted in multiple cancer types including ovarian cancer, providing justification of exploring the approaches to target the aberrations. In this study, we observed a spectrum of oncogenic phenotypes in ovarian cancer cells upon knockdown of PIK3R1 in vitro and in vivo, indicating the functional significance of PIK3R1 loss in ovarian cancer. Strikingly, PIK3R1 loss not only led to AKT activation (canonical signaling of PI3K), but also unexpectedly JAK2/STAT3 signaling activation (non-canonical signaling of PI3K). PIK3R1 loss induced translocation of STAT3 into the nucleus, where gene transcription was promoted and thereby the malignant properties. Using in vitro 3D culture spheroid assay, we found that PIK3R1 loss sensitized ovarian cancer cells to AKT inhibitors and JAK2/STAT3 inhibitors. More importantly, the combination of AKT and STAT3 inhibitors resulted in synergistic loss of cell viability. The demonstrated signaling alterations and the associated therapeutic susceptibility downstream of PIK3R1 loss may open new avenue for the treatment of PIK3R1 loss-bearing cancer. [This study was supported by Research Grants Council of the Hong Kong SAR, China, Project No. 27103616]
Persistent Identifierhttp://hdl.handle.net/10722/259098
ISSN
2017 Impact Factor: 9.13
2015 SCImago Journal Rankings: 5.372

 

DC FieldValueLanguage
dc.contributor.authorLi, X-
dc.contributor.authorMak, CY-
dc.contributor.authorZhou, Y-
dc.contributor.authorLu, Y-
dc.contributor.authorCheung, ANY-
dc.contributor.authorMills, GB-
dc.contributor.authorCheung, WTL-
dc.date.accessioned2018-09-03T04:01:28Z-
dc.date.available2018-09-03T04:01:28Z-
dc.date.issued2018-
dc.identifier.citationAmerican Association for Cancer Research Annual Meeting, Chicago, IL, 14-18 April 2018. In Cancer Research, 2018, v. 78 n. 13 Suppl, Abstract no. 3955-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/259098-
dc.description.abstractThe phosphoinositide 3-kinase (PI3K) regulatory subunit p85α is one of the critical gatekeepers of PI3K pathway activation through stabilizing and inhibiting the catalytic subunit p110. p85α is encoded by PIK3R1, which is frequently mutated or deleted in multiple cancer types including ovarian cancer, providing justification of exploring the approaches to target the aberrations. In this study, we observed a spectrum of oncogenic phenotypes in ovarian cancer cells upon knockdown of PIK3R1 in vitro and in vivo, indicating the functional significance of PIK3R1 loss in ovarian cancer. Strikingly, PIK3R1 loss not only led to AKT activation (canonical signaling of PI3K), but also unexpectedly JAK2/STAT3 signaling activation (non-canonical signaling of PI3K). PIK3R1 loss induced translocation of STAT3 into the nucleus, where gene transcription was promoted and thereby the malignant properties. Using in vitro 3D culture spheroid assay, we found that PIK3R1 loss sensitized ovarian cancer cells to AKT inhibitors and JAK2/STAT3 inhibitors. More importantly, the combination of AKT and STAT3 inhibitors resulted in synergistic loss of cell viability. The demonstrated signaling alterations and the associated therapeutic susceptibility downstream of PIK3R1 loss may open new avenue for the treatment of PIK3R1 loss-bearing cancer. [This study was supported by Research Grants Council of the Hong Kong SAR, China, Project No. 27103616]-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/-
dc.relation.ispartofCancer Research-
dc.titlePIK3R1 loss activates AKT and STAT3 signaling in ovarian cancer-
dc.typeConference_Paper-
dc.identifier.emailMak, CY: vicmak8@hku.hk-
dc.identifier.emailZhou, Y: yzhou@hku.hk-
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hk-
dc.identifier.emailCheung, WTL: lydiacwt@hku.hk-
dc.identifier.authorityCheung, ANY=rp00542-
dc.identifier.authorityCheung, WTL=rp02137-
dc.identifier.doi10.1158/1538-7445.AM2018-3955-
dc.identifier.hkuros288986-
dc.identifier.volume78-
dc.identifier.issue13 Suppl-
dc.identifier.spageAbstract no. 3955-
dc.identifier.epageAbstract no. 3955-
dc.publisher.placeUnited States-

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