PHGDH Is Upregulated at Translational Level and Implicated in Platin-Resistant in Ovarian Cancer Cells.
PHGDH Is Upregulated at Translational Level and Implicated in Platin-Resistant in Ovarian Cancer Cells.
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PHGDH 在翻译水平上调并与卵巢癌细胞的铂耐药有关
DOI：
10.3389/fonc.2021.643129
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发表时间：
2021
影响因子：
4.7
通讯作者：
Yang Q
中科院分区：
文献类型：
--
作者：
Bi F;An Y;Sun T;You Y;Yang Q
铂类化疗是卵巢癌的一线选择。对这种化疗的耐药性的发展导致治疗失败，而其潜在机制尚不清楚。临床标本来自中国医科大学附属盛京医院。MTT法检测卵巢癌细胞的增殖和耐药性。Transwell迁移和Matrigel侵袭实验检测卵巢癌细胞的侵袭能力。此外，还使用了多核糖体分析和组织芯片以及免疫组织化学染色。通过ANOVA和事后Dunnett检验分析差异的统计学显著性。PHGDH是负责丝氨酸生物合成途径的第一个酶。目前的研究表明，PHGDH在铂类耐药卵巢癌细胞和组织中在蛋白水平上上调。重要的是，PHGDH的敲低抑制，而PHGDH的过表达增加了顺铂暴露后卵巢癌细胞的存活率、侵袭力和球体形成。目前的研究表明，PHGDH翻译上调铂耐药卵巢癌。此外，我们的研究提供了证据表明，LncRNA RMRP（线粒体RNA加工核糖核酸内切酶的RNA组分）在铂类耐药卵巢癌中上调，这促进了RNA结合蛋白DDX 3X（DEAD-Box Helicase 3 X-Linked）在PHGDH mRNA上的富集，以促进其翻译。总的来说，目前的研究描述了PHGDH被上调并赋予卵巢癌细胞对顺铂的抗性，这表明顺铂抗性可以通过靶向PHGDH来克服。我们的研究还提供了证据表明，PHGDH蛋白的差异表达是由其翻译定义的，RNA结合蛋白DDX 3X和LncRNA RMRP是其翻译的调节因子。
Platinum-based chemotherapy is the first line option for ovarian cancer. The development of resistance to such chemotherapy results in treatment failure, while the underlying mechanisms are poorly understood. Clinical samples were collected from Shengjing Hospital of China Medical University. MTT assay was used to see the proliferation and chemoresistance of ovarian cancer cells. Transwell migration and Matrigel invasion assays was used to see the invasion ability of ovarian cancer cells. In addition, polysome profiling and tissue microarray and immunohistochemical staining were also used. The statistical significance of the difference was analyzed by ANOVA and post hoc Dunnett’s test. PHGDH is the first enzyme responsible for serine biosynthesis pathway. The current study demonstrated that PHGDH is upregulated in platin-resistant ovarian cancer cells and tissues at the protein level. Importantly, knockdown of PHGDH suppressed, while overexpression of PHGDH increased the survival upon cisplatin exposure, invasiveness and spheroid formation of ovarian cancer cells. The current study demonstrated that PHGDH translation was upregulated in platin-resistant ovarian cancer. In addition, our study provided evidence that LncRNA RMRP (RNA Component of Mitochondrial RNA Processing Endoribonuclease) was upregulated in platin-resistant ovarian cancer, which promoted enrichment of RNA binding protein DDX3X (DEAD-Box Helicase 3 X-Linked) on the PHGDH mRNA to promote its translation. Collectively, the current study described that PHGDH was upregulated and conferred resistance of ovarian cancer cells to cisplatin, suggesting that cisplatin resistance could be overcome by targeting PHGDH. Our study also provided evidence that differential PHGDH protein expression was defined by its translation, and RNA binding protein DDX3X and LncRNA RMRP are regulators of its translation.
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影响因子：
14.8
作者：
Pacold ME;Brimacombe KR;Chan SH;Rohde JM;Lewis CA;Swier LJ;Possemato R;Chen WW;Sullivan LB;Fiske BP;Cho S;Freinkman E;Birsoy K;Abu-Remaileh M;Shaul YD;Liu CM;Zhou M;Koh MJ;Chung H;Davidson SM;Luengo A;Wang AQ;Xu X;Yasgar A;Liu L;Rai G;Westover KD;Vander Heiden MG;Shen M;Gray NS;Boxer MB;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
4.1
作者：
Fullam, Anthony;Gu, Lili;Schroeder, Martina
通讯作者：
Schroeder, Martina
影响因子：
2.7
作者：
Mullarky, Edouard;Xu, Jiayi;Cantley, Lewis C.
通讯作者：
Cantley, Lewis C.
影响因子：
11.2
作者：
Samanta, Debangshu;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
影响因子：
11.2
作者：
Chen, Hung-Hsi;Yu, Hsin-I;Tarn, Woan-Yuh
通讯作者：
Tarn, Woan-Yuh