Oikawa Kosuke, Kuroda Masahiko, Ehata Shogo
Department of Pathology, School of Medicine, Wakayama Medical University, Wakayama 641-8509, Japan.
Department of Molecular Pathology, Tokyo Medical University, Tokyo 160-8402, Japan.
Biomed Rep. 2023 Jul 26;19(3):60. doi: 10.3892/br.2023.1642. eCollection 2023 Sep.
Suppression of the antitumor cytokine interleukin-24 (IL-24) is critical for the survival of myxoid liposarcoma (MLS) cells. It has been previously demonstrated by the authors that an MLS-specific chimeric oncoprotein, translocated in liposarcoma-CCAAT/enhancer-binding protein homologous protein (TLS-CHOP), supresses mRNA expression via induction of proteoglycan 4 (PRG4) to sustain MLS cell proliferation. However, IL-24 has also been revealed to be suppressed by the ubiquitin-proteasome system in human ovarian and lung cancer cells. Therefore, the aim of the present study was to elucidate the mechanism of IL-24 suppression in MLS cells. The results revealed that the proteasome inhibitor, MG-132, induced cell death in MLS cells ; this effect was reduced following IL-24 knockdown. This indicated that proteasomal degradation of IL-24 may be an important process for MLS cell survival. In addition, it was also previously revealed by the authors that knockdown of plasminogen activator inhibitor-1 (PAI-1), a TLS-CHOP downstream molecule, suppressed the growth of MLS cells, thus instigating the investigation of the effect of PAI-1 on IL-24 expression in MLS cells. Double knockdown of PAI-1 and IL-24 negated the growth-suppressive effect of PAI-1 single knockdown in MLS cells. Interestingly, PAI-1 single knockdown did not increase the mRNA expression of , but it did increase the protein abundance of IL-24, indicating that PAI-1 suppressed IL-24 expression by promoting its proteasomal degradation. Moreover, treatment of MLS cells with a PAI-1 inhibitor, TM5275, induced IL-24 protein expression and apoptosis. Collectively, the results of the present as well as previous studies indicated that IL-24 expression may be suppressed at the transcriptional level by PRG4 and at the protein level by PAI-1 in MLS cells. Accordingly, PAI-1 may represent an effective therapeutic target for MLS treatment.
抑制抗肿瘤细胞因子白细胞介素 - 24（IL - 24）对黏液样脂肪肉瘤（MLS）细胞的存活至关重要。作者先前已证明，一种MLS特异性嵌合癌蛋白，即易位至脂肪肉瘤的CCAAT/增强子结合蛋白同源蛋白（TLS - CHOP），通过诱导蛋白聚糖4（PRG4）来抑制mRNA表达，以维持MLS细胞增殖。然而，在人卵巢癌和肺癌细胞中，IL - 24也被揭示受到泛素 - 蛋白酶体系统的抑制。因此，本研究的目的是阐明MLS细胞中IL - 24抑制的机制。结果显示，蛋白酶体抑制剂MG - 132可诱导MLS细胞死亡；IL - 24基因敲低后，这种效应减弱。这表明IL - 24的蛋白酶体降解可能是MLS细胞存活的一个重要过程。此外，作者先前还发现，纤溶酶原激活物抑制剂 - 1（PAI - 1）（一种TLS - CHOP下游分子）的基因敲低可抑制MLS细胞的生长，从而促使研究PAI - 1对MLS细胞中IL - 24表达的影响。PAI - 1和IL - 24的双重基因敲低消除了PAI - 1单基因敲低对MLS细胞的生长抑制作用。有趣的是，PAI - 1单基因敲低并未增加IL - 24的mRNA表达，但确实增加了IL - 2蛋白丰度，表明PAI - 1通过促进其蛋白酶体降解来抑制IL - 24表达。此外，用PAI - 1抑制剂TM5275处理MLS细胞可诱导IL - 24蛋白表达和细胞凋亡。总体而言，本研究及先前研究的结果表明，在MLS细胞中，IL - 24的表达可能在转录水平受到PRG4的抑制，并在蛋白水平受到PAI - 1的抑制。因此，PAI - 1可能是MLS治疗的一个有效治疗靶点。
