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Inhibition of ovarian cancer cell growth by a novel TAK1 inhibitor LYTAK1

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An Erratum to this article was published on 08 October 2015

Abstract

Purpose

Transforming growth factor-β-activating kinase 1 (TAK1) has been implicated in promoting ovarian cancer progression. Here, we evaluated the anti-ovarian cancer effect of LYTAK1, a novel and specific TAK1 inhibitor.

Methods

Established or primary human ovarian cancer cells were treated with LYTAK1, and its cytotoxicity and underlying mechanisms were analyzed using in vitro and in vivo assays.

Results

We demonstrated that LYTAK1 blocked TAK1-nuclear factor kappa B activation, and potently inhibited growth of established (SKOV3, CaOV3 and A2780 lines) or primary (patient-derived) human ovarian cancer cells, where TAK1 was over-expressed and over-activated. While the normal ovarian epithelial cells (IOSE-80), with low TAK1 expression, were minimally affected by the same LYTAK1 treatment. In ovarian cancer cells, LYTAK1 mainly induced necrosis (but not apoptosis), which was associated with mitochondrial permeability transition pore (mPTP) opening, the latter was evidenced by mitochondrial membrane potential reduction. Inhibition of mPTP, either by its inhibitor sanglifehrin A or cyclosporine A, as well as by siRNA-mediated knockdown of cyclophilin-D or voltage-dependent anion channel, attenuated LYTAK1-induced necrosis and cytotoxicity in ovarian cancer cells. In vivo, LYTAK1 oral administration suppressed growth of SKOV3 xenografts in nude mice, and its activity could be further enhanced by co-treatment of paclitaxel (Taxol).

Conclusions

These data reveal the therapeutic potential of LYTAK1 as an agent targeting the pro-oncogenic TAK1 in ovarian cancer.

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Acknowledgments

This study was supported by the Scientific Research Project of Liaoning Province Department of Education.

Author contributions

All the listed authors carried out the experiments, participated in the design of the study, performed the statistical analysis, conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Central Laboratory, Maternal and Child Health Hospital of Jilin Province, Changchun, China

    Liu Ying

  2. Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Changchun, 555 West Wuma Road, Nanguan District, Changchun City, 130042, Jilin Province, China

    Yin Chunxia

  3. Department of Obstetrics and Gynecology, The PLA 222 Hospital, Jilin, China

    Liu Wei

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  1. Liu Ying
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  2. Yin Chunxia
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  3. Liu Wei
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Correspondence to Yin Chunxia.

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Ying, L., Chunxia, Y. & Wei, L. Inhibition of ovarian cancer cell growth by a novel TAK1 inhibitor LYTAK1. Cancer Chemother Pharmacol 76, 641–650 (2015). https://doi.org/10.1007/s00280-015-2822-8

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  • DOI: https://doi.org/10.1007/s00280-015-2822-8

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