IG20, a MADD splice variant, increases cell susceptibility to gamma-irradiation and induces soluble mediators that suppress tumor cell growth.
IG20, a MADD splice variant, increases cell susceptibility to gamma-irradiation and induces soluble mediators that suppress tumor cell growth.
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IG20 是一种 MADD 剪接变体，可增加细胞对伽马射线的敏感性，并诱导可溶性介质抑制肿瘤细胞生长。
作者：
E. Efimova;O. Martinez;A. Lokshin;T. Arima;B. Prabhakar
IG 20基因编码至少四种剪接变体，包括DENN-SV和IG 20。DENN-SV在肿瘤组织中以较高水平组成型表达。用DENN-SV cDNA转染的细胞显示出对肿瘤坏死因子α（TNF α）、TNF相关凋亡诱导配体（TRAIL）、依托泊苷和长春碱治疗的抗性增加，而IG 20的过表达增强了对内源性（药物）和外源性（例如，TNF α和TRAIL）死亡信号。在这项研究中，我们研究了IG 20的表达是否可以使细胞对γ射线敏感。与先前的结果一致，DENN-SV和IG 20在HeLa细胞中的过表达分别赋予了对γ-辐射作用的抗性和易感性。HeLa IG 20细胞的易感性可归因于增强的凋亡和减少的细胞生长。这种生长抑制由分泌的可溶性因子介导。尽管HeLa DENN-SV细胞比对照细胞生长更快，但用来自HeLa IG 20细胞的条件培养基补充抑制了它们的生长。此外，HeLa IG 20细胞的条件培养基使卵巢癌PA-1细胞的生长停止在G（1）-G（0）细胞周期阶段。在检测的一系列细胞因子中，在HeLa IG 20培养上清液中发现了最高水平的白细胞介素6（IL-6），并且IL-6中和显示其部分地负责细胞生长抑制。HeLa IG 20细胞具有升高的基础核因子kappaB水平，这是一种已知的IL-6转录调节因子。最后，IG 20过表达增强了TRAIL和γ射线对HeLa细胞的联合凋亡作用。这些结果表明，进一步了解IG 20剪接变异体的作用机制可能有助于癌症治疗的进展。
The IG20 gene encodes at least four splice variants, including DENN-SV and IG20. DENN-SV is constitutively expressed at higher levels in tumor tissues. Cells transfected with the DENN-SV cDNA show increased resistance to tumor necrosis factor alpha (TNFalpha), TNF-related apoptosis-inducing ligand (TRAIL), etoposide, and vinblastine treatment, whereas overexpression of IG20 enhanced susceptibility to both intrinsic (drugs) and extrinsic (e.g., TNFalpha and TRAIL) death signals. In this study, we investigated whether expression of the IG20 can render cells susceptible to gamma-irradiation. Consistent with previous results, overexpression of DENN-SV and IG20 in HeLa cells conferred resistance and susceptibility, respectively, to the effects of gamma-irradiation. HeLa IG20 cell susceptibility was attributable to enhanced apoptosis and reduced cell growth. This growth suppression was mediated by secreted soluble factors. Although HeLa DENN-SV cells grew more rapidly than control cells, replenishment with conditioned media from HeLa IG20 cells suppressed their growth. In addition, the conditioned media from HeLa IG20 cells stopped the growth of ovarian PA-1 cancer cells in the G(1)-G(0) cell cycle stage. Among an array of cytokines tested, interleukin 6 (IL-6) was found at the highest levels in HeLa IG20 culture supernatants, and IL-6 neutralization showed that it was, in part, responsible for the cell growth suppression. HeLa IG20 cells had elevated basal nuclear factor kappaB levels, a known regulator of IL-6 transcription. Finally, IG20 overexpression enhanced the combined apoptotic effects of TRAIL and gamma-irradiation on HeLa cells. These results suggest that understanding further the mechanism of action of the IG20 splice variant may help in the advancement of cancer therapies.
DOI：
10.1073/pnas.88.14.6028
发表时间：
1991-07-01
影响因子：
11.1
作者：
CORNIL, I;THEODORESCU, D;KERBEL, RS
通讯作者：
KERBEL, RS
影响因子：
20.3
作者：
A. Amanullah;B. Hoffman;D. Liebermann
通讯作者：
A. Amanullah;B. Hoffman;D. Liebermann