Matrine inhibits the growth of natural killer/T-cell lymphoma cells by modulating CaMKIIγ-c-Myc signaling pathway

Abstract

Background C-Myc overexpression is associated with poor prognosis and aggressive progression of natural killer/T-cell lymphoma (NKTCL). Matrine, a main alkaloid of the traditional Chinese herb Sophora flavescens Ait, has been shown to inhibit cellular proliferation and induce apoptosis of various cancer cells. The present study investigated the effects and possible mechanisms of matrine inhibiting the growth of natural killer/T-cell lymphoma cells. Methods The effects of matrine on the proliferation, apoptosis and expression of apoptotic molecules, STAT3, LMP1, RUNX3, EZH2 and activation of CaMKIIγ/c-Myc pathway were examined in cultured NKTCL cell line NK92 cells. Results In cultured NK92 cells, matrine inhibited the proliferation in a dose and time dependent manner. The IC 50 value of matrine was 1.71 mM for 72 h post exposure in NK92 cells. Matrine induced apoptosis with decreased Bcl-2 expression and the proteasome-dependent degradation of c-Myc protein in NK92 cells. c-Myc protein half-life in NK92 was reduced from 80.7 min to 33.4 min after matrine treatment, which meant the stability of c-Myc was decreased after matrine exposure. Furthermore, we found that matrine downregulated c-Myc phosphorylation at Ser62 together with the inhibition of CaMKIIγ, a key regulator of c-Myc protein in NKTCL. The downregulation of c-Myc transcription by matrine was mediated through LMP1 inhibition. We also observed that anti-proliferative activity of matrine was irrelevant to STAT3, RUNX3 and EZH2. Conclusions The results of the present study indicated that matrine inhibits the growth of natural killer/T-cell lymphoma cells by modulating LMP1-c-Myc and CaMKIIγ-c-Myc signaling pathway.

Matrine suppresses cell growth of diffuse large B-cell lymphoma via inhibiting CaMKIIγ/c-Myc/CDK6 signaling pathway

“…Ma et al showed that matrine suppressed the growth of human chronic myeloid leukemia K562 cells with an IC 50 of 2 mM for 48 h treatment [13]. Our previous study showed that matrine inhibited human NKTCL NK92 cells for 48 h with IC 50 of 1.96 mM [16]. In current study, matrine inhibited the growth of DLBCL cell lines SU-DHL-16 and OCI-LY3 cells in a dose and time dependent manner.…”

“…The cells were collected. Total RNA extraction, cDNA synthesis and qPCR were performed as described previously [16]. Brie y, total RNA was isolated by TRIzol.…”

“…Total cellular proteins extraction, SDS-PAGE and membrane transfer were processed step by step. Western blot was taken as described previously [16]. Brie y, membranes with proteins were blocked with 5% nonfat milk in TBS-Tween 20 (TBST).…”

“…CaMKIIγ was recently validated to be one of 102 potential genes involved in a synthetic lethal interaction with c-Myc [18]. CaMKIIγ phosphorylates c-Myc at Ser62 in T cell lymphoma and NKTCL [16,19]. The regulation of CaMKIIγ in matrine-treated DLBCL cells was then analyzed by western blot.…”

“…It possesses anti-in ammatory, anti-oxidant, antiviral and anti-allergic properties [12]. Recently, several reports showed that matrine has antihematological malignancy activities against leukemia, multiple myeloma, NK/T-cell lymphoma (NKTCL) [13][14][15][16]. However, the effect of matrine on DLBCL is still unknown.…”