Liu Ying1, Yin Chunxia, Liu Wei. 1. Central Laboratory, Maternal and Child Health Hospital of Jilin Province, Changchun, China.
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.
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 humanovarian 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) humanovarian 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.
Authors: Johan J N Veerman; Yorik B Bruseker; Eddy Damen; Erik H Heijne; Wendy van Bruggen; Koen F W Hekking; Rob Winkel; Christopher D Hupp; Anthony D Keefe; Julie Liu; Heather A Thomson; Ying Zhang; John W Cuozzo; Andrew J McRiner; Mark J Mulvihill; Peter van Rijnsbergen; Birgit Zech; Louis M Renzetti; Lee Babiss; Gerhard Müller Journal: ACS Med Chem Lett Date: 2021-03-03 Impact factor: 4.345