The complex role of transglutaminase 2 in glioblastoma proliferation
The complex role of transglutaminase 2 in glioblastoma proliferation
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DOI：
10.1093/neuonc/now157
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发表时间：
2017-02-01
期刊：
影响因子：
15.9
通讯作者：
Johnson, Gail V. W.
中科院分区：
文献类型：
--
作者：
Gundemir, Soner;Monteagudo, Alina;Johnson, Gail V. W.
背景。胶质母细胞瘤（GBMs）是一类异质性的原发性脑肿瘤。这些肿瘤对治疗干预有抵抗性，并且总是在手术切除后复发。多功能蛋白转谷氨酰胺酶2 （TG2）已被证明可促进许多不同肿瘤的细胞存活。也有证据表明，TG2可能是GBMs的促生存因子。然而，TG2在促进GBM存活和增殖中的作用尚未明确描述。TG2的功能通常与细胞和环境有关。因此，在本研究中，我们通过集落形成实验和5-乙基-2'-脱氧尿苷（EdU）在几种不同的GBM细胞系以及来自患者肿瘤的神经球中的结合，研究了TG2促进GBM增殖的能力，这些肿瘤代表了GBM肿瘤的3种主要亚型（间充质、原膜和经典），并在无血清的情况下维持。TG2敲除或选择性TG2抑制剂可调节TG2的表达和活性。我们发现TG2在不同细胞类型的增殖过程中起着不同的作用。在大多数（但不是全部）GBM模型中，TG2在增殖过程中起着至关重要的作用，并且在很大一部分GBM模型中，一些（但不是全部）TG2抑制剂在减少增殖方面非常有效。我们的研究结果表明，TG2在GBM细胞生物学中起着重要的作用，但众所周知，它具有环境特异性。尽管如此，随着未来的研究揭开使TG2抑制剂有效的遗传“指纹”，这一信息可以用于开发TG2抑制剂用于个性化GBM治疗。
Background. Glioblastomas (GBMs) are a heterogeneous group of primary brain tumors. These tumors are resistant to therapeutic interventions and invariably recur after surgical resection. The multifunctional protein transglutaminase 2 (TG2) has been shown to promote cell survival in a number of different tumors. There is also evidence that TG2 may be a pro-survival factor in GBMs. However, the roles that TG2 plays in facilitating GBM survival and proliferation have not yet been clearly delineated.Methods. The functions of TG2 are often cell-and context-specific. Therefore, in this study we examined the ability of TG2 to facilitate GBM proliferation using colony formation assays and 5-ethynyl-2'-deoxyuridine (EdU) incorporation in several different GBM cell lines as well as neurospheres derived from patient tumors representing the 3 major subtypes of GBM tumors (mesenchymal, proneural, and classical) and maintained in the absence of serum. TG2 knockdown or selective TG2 inhibitors were used to modulate TG2 expression and activity.Results. We show that TG2 plays differential roles in the proliferative process depending on the cell type. In most, but not all, GBM models TG2 plays a crucial role in the proliferative process, and some but not all TG2 inhibitors were highly effective at reducing proliferation in a large subset of the GBM models.Conclusion. Our results show that TG2 plays an important-but notoriously context-specific-role in GBM cell biology. Nonetheless, as future studies unravel the genetic " fingerprints" that make TG2 inhibitors effective, this information could be exploited to develop TG2 inhibitors into personalized GBM therapies.