MK-2206, an AKT Inhibitor, Promotes Caspase-Independent Cell Death and Inhibits Leiomyoma Growth

Endocrinology. 2013 Nov;154(11):4046-57. doi: 10.1210/en.2013-1389. Epub 2013 Sep 3.

Abstract

Uterine leiomyomas (ULs), benign tumors of the myometrium, are the number one indication for hysterectomies in the United States due to a lack of an effective alternative therapy. ULs show activation of the pro-survival AKT pathway compared with normal myometrium; however, substantial data directly linking AKT to UL cell survival are lacking. We hypothesized that AKT promotes UL cell survival and that it is a viable target for inhibiting UL growth. We used the investigational AKT inhibitor MK-2206, currently in phase II trials, on cultured primary human UL and myometrial cells, immortalized leiomyoma cells, and in leiomyoma grafts grown under the kidney capsule in mice. MK-2206 inhibited AKT and PRAS40 phosphorylation but did not regulate serum- and glucocorticoid-induced kinase and ERK1/2, demonstrating its specificity for AKT. MK-2206 reduced UL cell viability and decreased UL tumor volumes. UL cells exhibited disruption of mitochondrial structures and underwent cell death that was independent of caspases. Additionally, mammalian target of rapamycin and p70S6K phosphorylation were reduced, indicating that mammalian target of rapamycin complex 1 signaling was compromised by AKT inhibition in UL cells. MK-2206 also induced autophagy in UL cells. Pretreatment of primary UL cells with 3-methyladenine enhanced MK-2206-mediated UL cell death, whereas knockdown of ATG5 and/or ATG7 did not significantly influence UL cell viability in the presence of MK-2206. Our data provide molecular evidence for the involvement of AKT in UL cell survival and suggest that AKT inhibition by MK-2206 may be a viable option to consider for the treatment of ULs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Caspases / genetics
  • Caspases / metabolism*
  • Cell Death
  • Female
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Heterocyclic Compounds, 3-Ring / therapeutic use
  • Humans
  • Leiomyoma
  • Mice
  • Neoplasms, Experimental / drug therapy
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • RNA Interference
  • RNA, Small Interfering
  • Tissue Culture Techniques

Substances

  • Antineoplastic Agents
  • Heterocyclic Compounds, 3-Ring
  • MK 2206
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-akt
  • Caspases