PHGDH as a Key Enzyme for Serine Biosynthesis in HIF2α-Targeting Therapy for Renal Cell Carcinoma

Yoshino, Hirofumi; Nohata, Nijiro; Miyamoto, Kazuaki; Yonemori, Masaya; Sakaguchi, Takashi; Sugita, Sunao; Iwamoto, Toshihiko; Kofuji, Satoshi; Nakagawa, Masayuki; Dahiya, Rajvir; Enokida, Hideki

doi:10.1158/0008-5472.can-17-1589

Cited by 67 publications

(67 citation statements)

References 31 publications

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“…Disturbing PHGDH by siRNA or NCT-503, an inhibitor of PHGDH, the tumoricidal effect was improved and sensitivity to erlotinib was restored in cell lines and xenografts [90,91]. Additionally, suppression of PHGDH can eradicate advanced or metastatic clear cell renal cell carcinoma (ccRCC) resistant to HIF2α antagonists by inducing apoptosis [92]. PHGDH knocked down with RNAi and knocked out by CRISPR/Cas9 or inactivated by inhibitor can overcome tyrosine kinase inhibitor (TKI) drug resistance, including sorafenib, regorafenib, or lenvatinib, in hepatocellular carcinoma (HCC) [93].…”

Section: Phgdh and Tumor Resistance To Chemotherapy Drugsmentioning

confidence: 99%

The Role of D-3-Phosphoglycerate Dehydrogenase in Cancer

Zhao¹,

Fu²,

Du³

et al. 2020

Int. J. Biol. Sci.

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Serine, a non-essential amino acid, can be imported from the extracellular environment by transporters and de novo synthesized from glycolytic 3-phosphoglycerate (3-PG) in the serine biosynthetic pathway (SSP). It has been reported that active serine synthesis might be needed for the synthesis of proteins, lipids, and nucleotides and the balance of folate metabolism and redox homeostasis, which are necessary for cancer cell proliferation. Human D-3-phosphoglycerate dehydrogenase (PHGDH), the first and only rate-limiting enzyme in the de novo serine biosynthetic pathway, catalyzes the oxidation of 3-PG derived from glycolysis to 3-phosphohydroxypyruvate (3-PHP). PHGDH is highly expressed in tumors as a result of amplification, transcription, or its degradation and stability alteration, which dysregulates the serine biosynthesis pathway via metabolic enzyme activity to nourish tumors. And some recent researches reported that PHGDH promoted some tumors growth via non-metabolic way by upregulating target cancer-promoting genes. In this article, we reviewed the type, structure, expression and inhibitors of PHGDH, as well as the role it plays in cancer and tumor resistance to chemotherapy.

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Section: Phgdh and Tumor Resistance To Chemotherapy Drugsmentioning

confidence: 99%

The Role of D-3-Phosphoglycerate Dehydrogenase in Cancer

Zhao¹,

Fu²,

Du³

et al. 2020

Int. J. Biol. Sci.

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“…However, sunitinib therapy does not have curative effects due to RCC’s acquisition of resistance 4 . Moreover, our previous study showed the occurrence of metabolic re‐programming in RCC cells, leading to sunitinib resistance 5 . In November 2015, anti–programmed death‐1 (PD‐1) antibodies were approved for the treatment of patients with sunitinib‐resistant RCC.…”

Section: Introductionmentioning

confidence: 99%

Potential new therapy of Rapalink‐1, a new generation mammalian target of rapamycin inhibitor, against sunitinib‐resistant renal cell carcinoma

et al. 2020

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This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractSunitinib, a multitargeted receptor tyrosine kinase inhibitor including vascular endothelial growth factor, has been widely used as a first-line treatment against metastatic renal cell carcinoma (mRCC). However, mRCC often acquires resistance to sunitinib, rendering it difficult to treat with this agent. Recently, Rapalink-1, a drug that links rapamycin and the mTOR kinase inhibitor MLN0128, has been developed with excellent therapeutic effects against breast cancer cells carrying mTOR resistance mutations. The aim of the present study was to evaluate the in vitro and in vivo therapeutic efficacy of Rapalink-1 against renal cell carcinoma (RCC) compared to temsirolimus, which is commonly used as a small molecule inhibitor of mTOR and is a derivative of rapamycin. In comparison with temsirolimus, Rapalink-1 showed significantly greater effects against proliferation, migration, invasion and cFolony formation in sunitinib-naïve RCC cells. Inhibition was achieved through suppression of the phosphorylation of substrates in the mTOR signal pathway, such as p70S6K, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and AKT. In addition, Rapalink-1 had greater tumor suppressive effects than temsirolimus against the sunitinib-resistant 786-o cell line (SU-R 786-o), which we had previously established, as well as 3 additional SU-R cell lines established here. RNA sequencing showed that Rapalink-1 suppressed not only the mTOR signaling pathway but also a part of the MAPK signaling pathway, the ErbB signaling pathway and ABC transporters that were associated with resistance to several drugs. Our study suggests the possibility of a new treatment option for patients with RCC that is either sunitinib-sensitive or sunitinib-resistant. K E Y W O R D SmTOR inhibitor, Rapalink-1, renal cell carcinoma, sunitinib resistance, temsirolimus

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“…However, sunitinib therapy is not expected to have curative effects because it extends progression-free survival only slightly due to acquisition of resistance to sunitinib [ 4 ]. Moreover, metabolism re-programming was observed in RCC cell that showed sunitinib resistance to evade undesirable environment in our previous study [ 5 ]. Recently, anti-programmed death-1 (PD-1) antibodies were approved for the treatment of patients with advanced ccRCC.…”

Section: Introductionmentioning

confidence: 97%

“…Therefore, in this study, we aimed to investigate the anti-cancer efficiency of JQ1 in vitro and in vivo and to elucidate the molecular mechanisms underlying BRD4 inhibition in sunitinib-sensitive and -resistant ccRCC. First, we investigated the anti-cancer effects of JQ1 in vitro and in vivo using ccRCC cell lines, including sunitinib-resistant 786-o (SU-R-786-o), which we had previously established in vivo [ 5 ]. To identify key molecules in sunitinib-resistant ccRCC cells treated with JQ1, we performed RNA sequencing.…”

Section: Introductionmentioning

confidence: 99%

Bromodomain protein BRD4 inhibitor JQ1 regulates potential prognostic molecules in advanced renal cell carcinoma

et al. 2018

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Sunitinib is a standard molecular-targeted drug used as a first-line treatment for metastatic clear cell renal cell carcinoma (ccRCC); however, resistance to sunitinib has become a major problem in medical practice. Recently, bromodomain containing 4 (BRD4), a member of the bromodomain family proteins, was identified as a promising therapeutic target, and its inhibitor JQ1 has been shown to have inhibitory effects in various human cancers. However, the anti-cancer effects of JQ1 in ccRCC, particularly sunitinib-resistant ccRCC, are still unclear. Here, we aimed to elucidate the anti-cancer effects of JQ1 and the mechanisms underlying BRD4 inhibition in sunitinib-sensitive and -resistant ccRCCs. Analysis of The Cancer Genome Atlas (TCGA) ccRCC cohort showed that patients with high BRD4 expression had shorter overall survival than those with low expression. JQ1 treatment significantly inhibited tumor growth of sunitinib-sensitive and -resistant ccRCC cells in part through MYC regulation. Based on RNA sequencing analyses of ccRCC cells treated with JQ1 to elucidate the mechanisms other than MYC regulation, we identified several oncogenes that may be potential therapeutic targets or prognostic markers; patients with high expression of SCG5, SPOCD1, RGS19, and ARHGAP22 had poorer overall survival than those with low expression in TCGA ccRCC cohort. Chromatin immunoprecipitation assays revealed that these oncogenes may be promising BRD4 targets, particularly in sunitinib-resistant ccRCC cells. These results identified SCG5, SPOCD1, RGS19, and ARHGAP22 as potential prognostic markers and showed that BRD4 inhibition may have applications as a potential therapeutic approach in sunitinib-sensitive and -resistant ccRCC.

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PHGDH as a Key Enzyme for Serine Biosynthesis in HIF2α-Targeting Therapy for Renal Cell Carcinoma

Cited by 67 publications

References 31 publications

The Role of D-3-Phosphoglycerate Dehydrogenase in Cancer

The Role of D-3-Phosphoglycerate Dehydrogenase in Cancer

Potential new therapy of Rapalink‐1, a new generation mammalian target of rapamycin inhibitor, against sunitinib‐resistant renal cell carcinoma

Bromodomain protein BRD4 inhibitor JQ1 regulates potential prognostic molecules in advanced renal cell carcinoma

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