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Pitavastatin Selectively Kills PTEN Knock Out Cells and Cancer Organoids in Mouse Model via the Mevalonate Pathway
Author(s) -
Jiao Zhihua,
Cai Huaqing,
Long Yu,
Sirka Orit Katarina,
Ewald Andrew,
Devreotes Peter N
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.782.14
Subject(s) - pitavastatin , pten , cancer research , organoid , farnesyl pyrophosphate , pi3k/akt/mtor pathway , cancer cell , chemistry , geranylgeranyl pyrophosphate , cancer , microbiology and biotechnology , biology , prenylation , statin , medicine , signal transduction , biochemistry , atp synthase , enzyme
PTEN is one of the most frequently mutated tumor suppressors in human cancer. Loss of PTEN leads to hyperactivation of the PI3K–AKT signaling pathway, cell migration, and cell proliferation. Aiming to identify specific drugs that could target cancer cells, we screened 2650 FDA approved compounds and discovered that certain statins selectively kill Dictyostelium pten‐ cells. This result carries over to mammalian cells: MCF10A cells lacking PTEN are more sensitive to statins than MCF10A wild type (WT) cells. By testing the differential sensitivity between MCF10A WT and pten−/− cells with multiple statins, we found that pitavastatin showed the best performance. Mevalonic acid and geranylgeranyl pyrophosphate (GGPP), but not farnesyl phyrophosphate or squalene, rescued pitavastatin treated MCF10A pten−/− cells. Pitavastatin induced an increase in RhoA expression suggesting that the requirement for geranylgeranylation of this GTPase may mediate the sensitivity of MCF10A pten−/− cells. The different sensitivity between MCF10A WT and pten−/− cells also carried over to three‐dimensional culture model (3D). Moreover, we found pitavastatin significantly decreased the growth and Twist1‐induced cell dissemination in 3D culture of murine mammary gland organoids. Finally, we tested the effects of pitavastatin on growth and survival of WT( FVB ) and tumor organoids ( MMTV‐PyMT (luminal breast cancer model), C31Tag (basal breast cancer model)) in 3D culture. Both MMTV‐PyMT and C31Tag were killed by 100 nM pitavastatin, while WT organoids survived. These findings implicate pitavastatin as a potential therapeutic candidate for tumors. Support or Funding Information This work was supported by NIH Grant R35 GM118177. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .