β-Elemene suppresses tumor growth of diffuse large B-cell lymphoma through regulating lncRNA HULC-mediated apoptotic pathway

Abstract

Background: Diffuse large B-cell lymphoma (DLBCL) is considered the most common aggressive subtype of lymphoma. A number of DLBCL patients fail to achieve a response to currently available therapies or develop resistance. β-Elemene is derived from herb Curcuma wenyujin, and exhibits anti-tumor activity in both solid and non-solid tumors through modulating several molecular signaling pathways. We aimed to explore the role of β-elemene in DLBCL treatment and elucidate the involved mechanism. Materials and methods: Cell viability, apoptosis and expressions of related proteins were assessed and in vivo study were performed to determine the tumor suppressive effect of β-elemene and explore the molecular mechanisms. Results: β-Elemene significantly suppressed the viability of DLBCL cells, and β-elemene down-regulated the lncRNA HULC expression and regulated key pro-apoptotic and anti-apoptotic proteins to induce significant apoptosis of DLBCL cells. HULC overexpression could decrease the β-elemene induced apoptosis, while HULC knockdown increased the apoptosis in DLBCL cells. In vivo study further confirmed that β-elemene could suppress the growth of DLBCL xenograft and regulate the HULC expression and the critical proteins of the apoptotic pathway. Conclusion: β-Elemene performs as a tumor suppressor and modulator of HULC-mediated apoptotic pathway in DLBCL and will be an alternative candidate for clinical application.

<p>Long Noncoding RNAs in Diffuse Large B-Cell Lymphoma: Current Advances and Perspectives</p>

“…We anticipate that further in-depth investigation of the roles of lncRNAs in DLBCL might help unravel their intricate regulatory networks and provide important insights into DLBCL treatment. Maintain cell survival and inhibit apoptosis Not assessed [52] Note: "Not assessed" denotes that the direct targets or prognostic impacts of the lncRNAs were not assessed in the specific study. Abbreviations: HOTAIR, HOX transcript antisense RNA; FIRRE, functional intergenic repeating RNA element; NEAT1_1, nuclear paraspeckle assembly transcript 1_1; PANDA, p21-associated ncRNA DNA damage activated; lincRNA-p21, long intergenic noncoding RNA-p21; SNHG14, small nucleolar RNA host gene 14; SNHG16, small nucleolar RNA host gene 16; TUG1, taurine-upregulated gene 1; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; SMAD5-AS1, mothers against decapentaplegic homolog 5-antisense RNA 1; HULC, highly upregulated in liver cancer; EMT, epithelial-to-mesenchymal transition; H3K27me3, histone H3 trimethylation at lysine 27.…”

“…34 The lncRNA highly upregulated in liver cancer (HULC), which was originally found to be strongly overexpressed in human hepatocellular carcinoma, 51 is also involved in the pathogenesis of DLBCL. 52 Mechanistic data suggest that HULC can maintain cell survival and that the targeting of HULC by βelemene (a compound derived from the herb Curcuma wenyujin) can effectively suppress cell growth and induce apoptosis in DLBCL. 52 Cheng et al demonstrated that the overexpression of the lncRNA TUG1 has oncogenic effects in DLBCL, and this effects are mediated via direct interaction with the oncoprotein MET accompanied by inhibition of its subsequent ubiquitination and degradation.…”

“…52 Mechanistic data suggest that HULC can maintain cell survival and that the targeting of HULC by βelemene (a compound derived from the herb Curcuma wenyujin) can effectively suppress cell growth and induce apoptosis in DLBCL. 52 Cheng et al demonstrated that the overexpression of the lncRNA TUG1 has oncogenic effects in DLBCL, and this effects are mediated via direct interaction with the oncoprotein MET accompanied by inhibition of its subsequent ubiquitination and degradation. The targeting of TUG1 by gene knockdown can significantly suppress cell proliferation and tumor growth in DLBCL.…”

A Comprehensive Mini-Review of Curcumae Radix: Ethnopharmacology, Phytochemistry, and Pharmacology

“…β-Elemene (1-methyl-1-vinyl-2,4-diisopropenyl-cyclohexane), extracted from the root of Curcuma wenyujin , presents a broad-spectrum, moderate, antitumor effect and is widely used as an adjunctive drug to enhance the efficacy, reduce the toxicity of chemoradiotherapy, and reverse drug resistance in cancer treatment. 43 Previous studies have indicated that β‐elemene could inhibit cell proliferation and induce apoptosis in various types of cancers, including melanoma, 44 hepatocellular, 23 lymphoma, 26 glioma, 29 esophageal, 31 gastric, 45 glioblastoma multiforme, 32 nonsmall-cell lung, 33 pancreatic, 39 and nasopharyngeal. 34 Recent studies have reported that β‐elemene significantly inhibited the migration and invasive capacity of BGC823, SGC7901 and multidrug resistant (MDR) SGC7901/ADR gastric cancer cells, TE-1 and KYSE-150 esophageal cancer cells in vitro and inhibited the capacity of BGC823 cells to diffuse peritoneally and metastasize in vivo.…”

“…It modulated Ki67, PCNA, mitogen-activated protein kinase kinase-3 (MKK3), MKK-6, and cyclin proteins to arrest the cell cycle 31,35,38 and regulated the expression of relative proteins such as the long non-coding RNA (lncRNA) highly up-regulated in liver cancer (HULC), survivin, caspase-3,‐8 and −9, PERK, IRE1α, ATF6, Hsp90/Raf-1, Fas/FasL, and Bcl-2/BAX proteins to induce cell apoptotic death of cancer cells. 26,27,29,33,35,37 In addition, β-elemene performed synergistic or directly suppressive effects through targeting histone H1, 23 copper transporter 1 (CTR1), 30 E3 ubiquitin ligase Cbl, 36 signal transducer, and activator of transcription 3 (Stat3), DNA methyltransferase 1 (DNMT1), enhancer of zeste homolog 2 (EZH2), 34 hypoxia inducible factor 1 subunit α (HIF1α), vascular endothelial growth factor A (VEGFA), 39 PTEN, 31 and ataxia telangiectasia mutated (ATM) signaling pathways. 32 Furthermore, β-elemene inhibited tumor angiogenesis and metastasis through regulation of crucial molecules, such as Claudin-1 by downregulating FAK phosphorylation, 24 MMP-2/9 via modulating Cbl-b/EGFR/ERK/AKT signaling 25 and programmed cell death 1-ligand 1 (PD-L1) by regulating p-AKT.…”