title: Inhibition of ovarian cancer cell growth by a novel TAK1 inhibitor LYTAK1.
abstract: OBJECTIVE
  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.
authors.affiliation: Central Laboratory, Maternal and Child Health Hospital of Jilin Province, Changchun, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Ying
authors.forename: Yin
authors.initials: Y
authors.lastname: Chunxia
authors.forename: Liu
authors.initials: L
authors.lastname: Wei
mesh_terms: D000818:Animals; D001201:Ascites / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011897:Random Allocation; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D000099151:MAP Kinase Kinase Kinase 7