Y-box binding protein-1 and STAT3 independently regulate ATP-binding cassette transporters in the chemoresistance of gastric cancer cells

Chua,Pei Jou; Lim,Jia Pei; Guo,Tian Tian; Khanna,Puja; Hu,Qidong; Bay,Boon Huat; Baeg,Gyeong Hun

doi:10.3892/ijo.2018.4557

Y-box binding protein-1 and STAT3 independently regulate ATP-binding cassette transporters in the chemoresistance of gastric cancer cells

Authors:
- Pei Jou Chua
- Jia Pei Lim
- Tian Tian Guo
- Puja Khanna
- Qidong Hu
- Boon Huat Bay
- Gyeong Hun Baeg
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Affiliations: Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore
Published online on: September 11, 2018 https://doi.org/10.3892/ijo.2018.4557
Pages: 2579-2589

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Abstract

Y-box binding protein-1 (YB-1) facilitates cancer chemoresistance through the upregulation of ATP-binding cassette (ABC) transporters associated with multidrug resistance, which is one of the primary obstacles in cancer treatment. Since aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is also implicated in chemoresistance in numerous human malignancies, the interaction between YB-1 and JAK/STAT signaling was explored underlying the chemoresistance of NUGC3 gastric cancer cells. It was demonstrated that YB-1 translocated into the nuclei of NUGC3 cells exposed to doxorubicin hydrochloride, suggesting its important role in chemoresistance. Consistently, knockdown of YB-1 significantly decreased the chemoresistance of cells to doxorubicin hydrochloride and epirubicin hydrochloride, as evidenced by a decrease in cell viability. Notably, JAK inhibitor AG490 treatment further decreased the cell viability caused by YB-1 inhibition and doxorubicin hydrochloride. It was also observed that YB-1 transcriptionally regulated the ABCC3 transporter, whereas STAT3 modulated ABCC2 transporter levels. These findings suggest that YB-1 and STAT3 act together to facilitate chemoresistance via modulating the expression of different ABC transporters in NUGC3 cells. Notably, siYB-1 did not exhibit any significant effect on STAT3 expression. Similarly, siSTAT3 failed to alter YB-1 expression, suggesting that the two may not regulate each other in a mutual manner. However, double knockdown of YB-1 and STAT3 led to a synergistic inhibition of cell invasion in NUGC3 cells. Nonetheless, the combined treatment of YB-1 antagonists with STAT3 inhibitors may serve as an effective therapy in gastric cancer.

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