Glycine Decarboxylase Activity Drives Non-Small Cell Lung Cancer Tumor-Initiating Cells and Tumorigenesis

Zhang, Wen Cai; Shyh‐Chang, Ng; He, Ya‐Ling; Rai, Amit; Umashankar, Shivshankar; Ma, Shiying; Soh, Boon Seng; Sun, Li; Tai, Bee Choo; Nga, Min En; Bhakoo, Kishore; Jayapal, Senthil Raja; Nichane, Massimo; Q, Yu; Ahmed, Dokeu A.; Tan, C. B.; Sing, Wong Poo; Tam, John S.; Agasthian, Thirugnanam; Noghabi, Monireh Soroush; Pang, Yin Huei; Ang, Haw Siang; Mitchell, Wayne; Robson, P. R. H.; Kaldis, Philipp; Soo, Ross A.; Swarup, Sanjay; Lim, Elaine; Lim, Bing

doi:10.1016/j.cell.2012.02.024

Cited by 112 publications

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“…Notably, a recent study showed that the expression of PSAT1 was upregulated in lung tumor-initiating cells and PSAT1 could transform 3T3 cells to form tumor in vivo. 13 Nevertheless, the expression and biological function of PSAT1 in NSCLC are largely unknown. The current study provides strong evidence that PSAT1 is over-expressed in NSCLC based on the following findings: (i) comparative analysis of 89 pairs of primary tumors and adjacent normal tissues deposited in the TCGA dataset showed that PSAT1 expression is significantly elevated in tumor tissues; (ii) qRT-PCR assay with 20 pairs of tumor and adjacent nontumorous lung tissues exhibited similar results to that derived from the TCGA dataset; (iii) IHC assessment of 138 paraffin embedded, archived tissue specimens demonstrated that PSAT1 is overexpressed in NSCLC and its up-regulation is associated with poor prognosis of the disease.…”

Section: Discussionmentioning

confidence: 99%

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PSAT1 regulates cyclin D1 degradation and sustains proliferation of non‐small cell lung cancer cells

Yang

Cai

et al. 2014

Intl Journal of Cancer

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Multiple nodes in the one-carbon metabolism pathway play important regulatory roles in cancer cell growth and tumorigenesis. The specific biological functions of metabolic enzymes in regulating the signaling pathways that are associated with tumor cell growth and survival, however, remain unclear. Our current study found that phosphoserine aminotransferase 1 (PSAT1), an enzyme catalyzing serine biosynthesis, was significantly up-regulated in non-small cell lung cancer (NSCLC) and was involved in the regulation of E2F activity. Loss-and gain-of-function experiments demonstrated that PSAT1 promoted cell cycle progression, cell proliferation and tumorigenesis. Mechanistic study suggested that elevated PSAT1 led to inhibition of cyclin D1 degradation and subsequently an alteration in Rb-E2F pathway activity, which in turn enhanced G1 progression and proliferation of NSCLC cells. Moreover, phosphorylation of cyclin D1 at threonine 286 by GSK-3b was required for PSAT1-induced blockage of cyclin D1 degradation. We also found that the activity of p70S6K mediated the effects of PSAT1 on GSK3b phosphorylation and cyclin D1 degradation. We further identified that PSAT1 was over-expressed in NSCLC and predicted poor clinical outcome of patients with the disease. Correlation analysis showed that PSAT1 expression positively correlated with the levels of phosphorylated GSK-3b, cyclin D1 and phosphorylated Rb in NSCLC primary tumors. These findings uncover a mechanism for constitutive activation of E2F via which unrestrained cell cycle progression occurs in NSCLC and may represent a prognostic biomarker and therapeutic target.Malignant tumor is essentially a disease involving unlimited cell proliferation.1,2 To obtain limitless replicative potential, cancer cells not only need to sustain growth-stimulatory signals, but also must circumvent powerful anti-proliferative limits.3 At the molecular level, signals mediated by the retinoblastoma protein (Rb) significantly contribute to the growth-inhibition of cells prone to malignancy development.4,5 The Rb protein operates as a pivotal regulator of G0/G1 to S phase transition of the cell cycle and tumorigenesis. 6 When in a hypophosphorylated state, Rb protein suppresses the G1/S transition by sequestering the activity of E2F family of transcription factors that control the expression of genes essential for cell-cycle regulation. 7 In contrast, hyperphosphorylation of Rb leads to release of E2F,

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Section: Discussionmentioning

confidence: 99%

“…12 It has been well documented that many key oncogene and tumor suppressor networks can influence tumor cell metabolism and eventually support proliferation. 13 Nevertheless, the role of metabolic enzymes themselves in modulating the signaling pathways associated with tumor cell growth and survival is largely unclear.…”

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confidence: 99%

PSAT1 regulates cyclin D1 degradation and sustains proliferation of non‐small cell lung cancer cells

Yang

Cai

et al. 2014

Intl Journal of Cancer

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“…40 The heterogeneity of CSCs has also been found in other cancers, including glioblastoma, 41 prostate cancer, 42 and lung cancer. 43 The heterogeneity of CSCs is so complex that more effective biomarkers are needed to identify CSCs or distinguish the heterogeneity of CSCs.…”

Section: The Concept Of Cscs Biological Characteristics Of Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,113

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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“…Curiously, a link between glycine metabolism and tumorigenesis has also been reported, although there might be several metabolic changes that can support cell growth. 29 The observed transcriptional profile changes were mirrored by higher levels of cell migration and invasion potential of MCPH1 mutant cells. Moreover, in 3D culture, MCPH1 mutants formed larger spheroids than controls.…”

Section: Discussionmentioning

confidence: 94%

“…Multiple components of the glycine/serine pathway have been proposed to act as metabolic oncogenes. 29 Other upregulated genes included MSLN, a cell adhesion protein overexpressed in epithelial mesotheliomas and ovarian cancers, 30 and FRMD3, a cytoskeletal binding protein that acts as a putative tumor suppressor in lung cancer. 31…”

Section: Mcph1 Mutated Cells Show Alteration In Gene Expression Profilesmentioning

confidence: 99%

Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly

Tervasmäki

Mantere

Eshraghi

et al. 2019

Intl Journal of Cancer

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Strong inherited predisposition to breast cancer is estimated to cause about 5–10% of all breast cancer cases. As the known susceptibility genes, such as BRCA1 and BRCA2, explain only a fraction of this, additional predisposing genes and related biological mechanisms are actively being searched for. We have recently identified a recurrent MCPH1 germline mutation, p.Arg304ValfsTer3, as a breast cancer susceptibility allele. MCPH1 encodes a multifunctional protein involved in maintenance of genomic integrity and it is also somatically altered in various cancer types, including breast cancer. Additionally, biallelic MCPH1 mutations are causative for microcephaly and at cellular level premature chromosome condensation. To study the molecular mechanisms leading to cancer predisposition and malignant conversion, here we have modeled the effect of MCPH1 p.Arg304ValfsTer3 mutation using gene‐edited MCF10A breast epithelial cells. As a complementary approach, we also sought for additional potential cancer driver mutations in MCPH1 p.Arg304ValfsTer3 carrier breast tumors. We show that mutated MCPH1 de‐regulates transcriptional programs related to invasion and metastasis and leads to downregulation of histone genes. These global transcriptional changes are mirrored by significantly increased migration and invasion potential of the cells as well as abnormal chromosomal condensation both before and after mitosis. These findings provide novel molecular insights to MCPH1 tumor suppressor functions and establish a role in regulation of transcriptional programs related to malignant conversion and chromosomal assembly. The MCPH1 p.Arg304ValfsTer3 carrier breast tumors showed recurrent tumor suppressor gene TP53 mutations, which were also significantly over‐represented in breast tumors with somatically inactivated MCPH1.

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Glycine Decarboxylase Activity Drives Non-Small Cell Lung Cancer Tumor-Initiating Cells and Tumorigenesis

Cited by 112 publications

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PSAT1 regulates cyclin D1 degradation and sustains proliferation of non‐small cell lung cancer cells

PSAT1 regulates cyclin D1 degradation and sustains proliferation of non‐small cell lung cancer cells

Targeting cancer stem cell pathways for cancer therapy

Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly

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