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Inhibition of JAK2 Reverses Paclitaxel Resistance in Human Ovarian Cancer Cells. Int J Gynecol Cancer 2015 Nov;25(9):1557-64

Date

09/12/2015

Pubmed ID

26360705

DOI

10.1097/IGC.0000000000000550

Scopus ID

2-s2.0-84946036975   13 Citations

Abstract

OBJECTIVE: Resistance to chemotherapy is a major factor that limits the postsurgical survival of ovarian cancer patients. Janus-activated kinase 2 (JAK2) has been implicated in cancer cell survival and the development of drug resistance in ovarian cancers. In the present study, we sought to determine whether inhibition of JAK2 reverses drug resistance in OC3/TAX300 cells, a paclitaxel-resistant human ovarian cancer cell line previously established in our laboratory.

METHODS: OC3/TAX300 cells were transduced with lentivirus expressing small interference RNA (siRNA) against JAK2 and treated with JAK2 kinase inhibitor AG490.

RESULTS: Treatment with JAK2-siRNA markedly decreased the messenger RNA and protein of JAK2 as determined by real-time polymerase chain reaction and Western blot analysis. OC3/TAX300 cells treated with JAK2-siRNA exhibited stalled growth, increased cell cycle arrest in G2/M phase, and enhanced apoptosis in response to paclitaxel. In keeping with this, JAK2-siRNA also inhibited the expression of multidrug resistance protein 1. To determine whether JAK2 promotes paclitaxel resistance via phosphorylation of signal transducer and activator of transcription 3 (STAT3), a transcription factor known to be involved in resistance to chemotherapy, we treated OC3/TAX300 cells with JAK2 kinase inhibitor AG490. Of note, AG490 reduced the level of p-STAT3 and inhibited the expression of multidrug resistance protein 1 in a dose-dependent manner.

CONCLUSIONS: Collectively, we conclude that the JAK2-STAT3 pathway promotes the development of paclitaxel resistance via upregulating the expression of prosurvival and antiapoptotic genes. Targeting this pathway may be effective in reversing resistance to chemotherapy in ovarian cancers.

Author List

Xu Y, Zhang J, Wu J, Zhong S, Li H



MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents, Phytogenic
Apoptosis
Cell Proliferation
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Enzyme Inhibitors
Female
G2 Phase Cell Cycle Checkpoints
Gene Expression Regulation, Neoplastic
Humans
Janus Kinase 2
M Phase Cell Cycle Checkpoints
Ovarian Neoplasms
Paclitaxel
Phosphorylation
RNA, Messenger
RNA, Small Interfering
STAT2 Transcription Factor
Signal Transduction
Transduction, Genetic
Tyrphostins
Up-Regulation