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Int. J. Mol. Sci. 2017, 18(1), 179; doi:10.3390/ijms18010179

A Novel Combination RNAi toward Warburg Effect by Replacement with miR-145 and Silencing of PTBP1 Induces Apoptotic Cell Death in Bladder Cancer Cells

1
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
2
Department of Urology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
3
Department of General and Gastroenterological Surgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
4
Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Martin Pichler
Received: 3 October 2016 / Revised: 27 December 2016 / Accepted: 10 January 2017 / Published: 17 January 2017
(This article belongs to the Collection Regulation by Non-Coding RNAs)
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Abstract

Bladder cancer is one of the most difficult malignancies to control. We explored the use of a novel RNA-interference method for a driver oncogene regulating cancer specific energy metabolism by the combination treatment with a small interfering RNA (siRNA) and a microRNA. After transfection of T24 and 253JB-V cells with miR-145 and/or siR-PTBP1, we examined the effects of cell growth and gene expression by performing the trypan blue dye exclusion test, Western blot, Hoechst 33342 staining, reverse transcription polymerase chain reaction (RT-PCR), and electron microscopy. The anti-cancer effects of xenograft model mice with miR-145 and/or siR-PTBP1 were then assessed. The combination treatment induced the deeper and longer growth inhibition and reduced the levels of both mRNA and protein expression of c-Myc and polypyrimidine tract-binding protein 1 (PTBP1) more than each single treatment. Notably, the combination treatment not only impaired the cancer specific energy metabolism by inhibiting c-Myc/PTBP1/PKMs axis but also inactivated MAPK/ERK and PI3K/AKT pathways examined in vitro and in vivo. Furthermore, the combination treatment induced apoptosis or autophagy; but, in some cells, apoptotic cell death was accompanied by autophagy, because the condensation of chromatin and many autophagosomes were coexistent. This combination treatment could be a novel RNA-interference strategy through the systemic silencing of the Warburg effect-promoting driver oncogene PTBP1 in bladder cancer cells. View Full-Text
Keywords: bladder cancer; c-Myc/PTBP1/PKMs axis; combination RNA-interference treatment; miR-145; Warburg effect bladder cancer; c-Myc/PTBP1/PKMs axis; combination RNA-interference treatment; miR-145; Warburg effect
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Takai, T.; Yoshikawa, Y.; Inamoto, T.; Minami, K.; Taniguchi, K.; Sugito, N.; Kuranaga, Y.; Shinohara, H.; Kumazaki, M.; Tsujino, T.; Takahara, K.; Ito, Y.; Akao, Y.; Azuma, H. A Novel Combination RNAi toward Warburg Effect by Replacement with miR-145 and Silencing of PTBP1 Induces Apoptotic Cell Death in Bladder Cancer Cells. Int. J. Mol. Sci. 2017, 18, 179.

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