PHGDH Is Upregulated at Translational Level and Implicated in Platin-Resistant in Ovarian Cancer Cells

Abstract

BackgroundPlatinum-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.MethodsClinical 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.ResultsPHGDH 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.ConclusionCollectively, 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.

High Mobility Group A1 (HMGA1): Structure, Biological Function, and Therapeutic Potential

“…Surgical resection and cisplatin chemotherapy are the preferred choices for the treatment of ovarian cancer, but because early screening factors are not obvious, symptoms only appear in the late stage, and the 5-year survival rate can be as low as 30% 59 , 60 . At present, studies have found that HMGA1 can regulate the expression of stem-related genes in ovarian cancer, such as KLF4, SOX2 and ABCG2, a drug-resistant protein, increasing the resistance of ovarian cancer to paclitaxel 61 .…”

RNA-binding proteins in ovarian cancer: a novel avenue of their roles in diagnosis and treatment

“…The RBP of DEAD-Box Helicase 3X-Linked (DDX3X) can be stabilized by RNA Component of Mitochondrial RNA Processing Endoribonuclease (lncRNA RMRP) and promotes Phosphoglycerate dehydrogenase (PHGDH) mRNA translation, thus conferring resistance of OC cells and inhibiting OC progression [ 80 ]. Overexpression of DDX3X can reverse miR-196a-mediated OC progression by activating PTEN expression and suppressing AKT activity [ 81 ].…”

Ovarian Aging: Role of Pituitary-Ovarian Axis Hormones and ncRNAs in Regulating Ovarian Mitochondrial Activity

“…Another example is the RNA component of the RNA processing endoribonuclease (RMRP) transported by RNA binding proteins such as GRSF1 localized in RNA granules. In spite of the fact that it has not been investigated in follicle maturation and/or aging, it has been shown increased in platin-resistant ovarian cancers ( 90 ). In other tissues, it is described as p53 inhibitor ( 91 ).…”