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Icaritin inhibits PLK1 to activate DNA damage response in NK/T cell lymphoma and increases sensitivity to GELOX regime

ABSTRACT: NK/T cell lymphoma (NKTCL) is a highly aggressive subtype of non-Hodgkin lymphoma. GELOX (gemcitabine, oxaliplatin, and L-asparaginase) is one of the first-line chemotherapy regimens of NKTCL. Yet, the prognosis of NKTCL is poor. Icaritin (ICT) is an herb-derived monomer from icariin with antitumor effects. We found that icaritin induced proliferation inhibition and apoptosis of NKTCL both in vitro and in vivo. Moreover, icaritin inhibited the dissemination of NKTCL in vivo. RNA sequencing (RNA-seq) revealed the polo-like kinase 1 (PLK1) gene and DNA damage response (DDR) as the targets of icaritin. Mechanistically, icaritin inhibited PLK1 to promote checkpoint kinase 2 (Chk2) homodimerization and its T387 phosphorylation, which further activated p53, leading to the activation of the DDR pathway. Moreover, inhibiting PLK1 increased Forkhead box O3a (FOXO3a) nuclear localization, the latter of which activated Ataxia-telangiectasia mutated (ATM), an early sensor of DNA damage. Then ATM phosphorylated Chk2 T68 and initiated Chk2 activation. Remarkably, combined treatment of icaritin and GELOX achieved better antitumor efficacy than single treatment in vivo. In summary, our results proved the efficacy of icaritin treating NKTCL, and provided insights into its antitumor molecular mechanism, and revealed the application value of icaritin in facilitating clinical NKTCL treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201959 | GEO | 2022/05/04

REPOSITORIES: GEO

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Project description:Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM-Chk1/Chk2-p53/p21 checkpoint and cellular senescence at early stages of cellular transformation caused by a regulatable MLL-ENL-ERtm in mice. Furthermore, we identified the transcription program underlying this intrinsic anti-cancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling towards senescence, thereby modulating the fate of MLL-ENL-immortalized cells in a tissue-environment-dependent manner. Our results indicate that DDR is a rate-limiting event for acquisition of stem cell-like properties in MLL-ENL-ERtm-mediated transformation, as experimental inhibition of the barrier accelerated the transition to immature cell states and acute leukemia development. We created a mouse model wherein the protein function of the MLL-ENL oncogene depends on tamoxifen due to fusion with the mutated estrogen-binding domain of the estrogen receptor (ERtm). After 7 months of tamoxifen administration, the MLL-ENL-ERtm mice developed a myeloproliferative disease, which progressed into the terminal stage after a long period (mean survival: 592 ± 112 days) of continuous tamoxifen provision. We have profiled gene expression at three time-points of tamoxifen treatment corresponding to three distinct cellular states of the MLL-ENL-ERtm-induced myeloproliferation in the bone marrow: 1. 7 months - high proliferation state with low DDR signaling (4 biological replicates), 2. 7-8 months - the transition period of lower proliferation and high DDR activity (4 biogical replicates) and 3. 8 months - the senescence (3 biological replicates). Time-matched tamoxifen-treated wild-type bone marrow analysed in 4 biological replicates. We have profiled gene expression in three disease stages in the spleen: 1. 7 months - early stage - induced proliferation and DDR (3 biological replicates), 2. 9-10 months - progression - partial senescence and DDR is maintained (3 biological replicates) and 3. 16-23 months - terminal stage - proliferation, low or absent DDR and no senescence (3 biological replicates). Time-matched tamoxifen-treated and age-matched wild-type spleens analysed in 5 biological replicates.

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Icaritin inhibits PLK1 to activate DNA damage response in NK/T cell lymphoma and increases sensitivity to GELOX regime

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