Deficiency of FLCN in Mouse Kidney Led to Development of Polycystic Kidneys and Renal Neoplasia

Chen, Jindong; Futami, Kunihiko; Petillo, David; Peng, Jun; Wang, Pengfei; Knol, Jared; Li, Yan; Khoo, Sok Kean; Huang, Dan; Qian, Chao Nan; Zhao, Ping; Dykyma, Karl; Zhang, Racheal; Cao, Brian; Yang, Ximing J.; Furge, Kyle A.; Williams, Bart O.; Teh, Bin Tean

doi:10.1371/journal.pone.0003581

Cited by 125 publications

(135 citation statements)

References 33 publications

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“…MYC inactivation reversed their neoplastic features associated with arrest, apoptosis, and senescence. RCC has been associated with mutations in many gene products, such as tumor suppressor genes, the Von Hippel-Lindau (VHL) gene and oncogenes such as the tyrosine kinase receptor (MET) (3,(41)(42)(43)(44)(45)(46)(47)(48) and mutation of PI3K (5). Notably, PI3K appears to maintain neoplasia via MYC (49).…”

Section: Discussionmentioning

confidence: 99%

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

Shroff¹,

Eberlin

Dang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

217

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The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show through a conditional transgenic mouse model that the MYC oncogene, but not the RAS oncogene, initiates and maintains RCC. Desorption electrospray ionization-mass-spectrometric imaging was used to obtain chemical maps of metabolites and lipids in the mouse RCC samples. Gene expression analysis revealed that the mouse tumors mimicked human RCC. The data suggested that MYC-induced RCC up-regulated the glutaminolytic pathway instead of the glycolytic pathway. The pharmacologic inhibition of glutamine metabolism with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide impeded MYC-mediated RCC tumor progression. Our studies demonstrate that MYC overexpression causes RCC and points to the inhibition of glutamine metabolism as a potential therapeutic approach for the treatment of this disease.MYC oncogene | renal cell carcinoma | desorption electrospray ionization mass spectrometry imaging | glutamine metabolism R enal cell adenocarcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport waste molecules from the blood to the urine. Most patients who present with advanced RCC have a dismal prognosis because RCC easily metastasizes and advances in therapy have been limited (1-3). A lack of transgenic models of RCC has made it difficult to identify and test new therapeutic modalities.The MYC pathway is activated in most cases of human RCC (4), genomically amplified in 5-10% of patients, overexpressed in 20% (5), and associated with a hereditary RCC syndrome (6) suggesting a causal role in the pathogenesis, but this has never been examined. Here, we report the development of a conditional transgenic mouse model for MYC-deregulated human RCC. The MYC oncogene contributes to tumorigenesis of many types of cancer through various mechanisms (7-10), including the regulation of proliferation and growth, protein and ribosomal biogenesis, changes in metabolism, lipid synthesis, and induction of angiogenesis (11)(12)(13)(14). MYC reprogramming can result in tumors that are addicted to glucose and/or glutamine for their energy metabolism (15-19). MYC directly regulates specific genes of the glycolytic and glutaminolytic pathways (15,17,20,21), including lactate dehydrogenase A (LDHA), glucose transporter 1 (Glut1), hexokinase 2 (HK2), phosphofructokinase-M 1 (PFKM1), and enolase 1 (Eno1) (21-23). Also, MYC coordinates genes involved in glutamine catabolism (SI MYC and Glutamine Catabolism). However, there has been no evidence to show that MYC overexpression directly drives and maintains RCC or how this occurs.Through our new transgenic mouse model, we showed that transgenic MYC, but not mutant RAS, overexpression in vivo rapidly initiates a highly aggressive RCC that histologi...

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Section: Discussionmentioning

confidence: 99%

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

Shroff¹,

Eberlin

Dang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

217

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“…Based on its position in this pathway, folliculin could hold a nutrient-/energy-sensing role [19]. In several other studies, loss of FLCN function was associated with mTORC1 and phosphorylated ribosomal protein S6 (pS6) activity during renal cystogenesis and tumorigenesis [19,21,22]. Based on the sum of these data, mTOR inhibitors may represent a rational therapeutic approach in this disease process.…”

Section: Birt-hogg-dubé Syndromementioning

confidence: 99%

Tumor Biology and Prognostic Factors in Renal Cell Carcinoma

2011

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In the past 15 years, there has been an increased understanding of the tumor biology of renal cell carcinoma (RCC). The identification of vascular endothelial growth factor (VEGF), its related receptor (VEGFR), and the mammalian target of rapamycin as dysregulated signaling pathways in the development and progression of RCC has resulted in the rational development of pharmaceutical agents capable of specifically targeting key steps in these pathways. Clinical trials have demonstrated survival benefit with these agents, particularly in clear cell RCC patients. However, metastatic RCC will progress in all patients, resulting in a critical need to determine patient risk and optimize treatment. The goal of this article is to highlight the significant breakthroughs made in understanding the critical genetic alterations and signaling pathways underlying the pathogenesis of RCC. The discovery of prognostic factors and development of comprehensive nomograms to stratify patient risk and predictive biomarkers to facilitate individualized treatment selection and predict patient response to therapy also are reviewed. The Oncologist 2011;16(suppl 2):4 -13

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“…Although the precise function of the FLCN gene product is still being elucidated, FLCN (and the folliculin interacting proteins FNIP1 and FNIP2) have been linked to the mTOR and AMPK signaling pathways (13)(14)(15). In mice with kidney-targeted homozygous inactivation of Flcn renal tumors and cysts developed with activation of mTOR and the mTOR inhibitor rapamycin diminished kidney pathology and increased survival (16,17).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Targeting the Loss of the Birt-Hogg-Dubé Suppressor Gene

Lü

Wei

Fenton

et al. 2011

Molecular Cancer Therapeutics

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Brit-Hogg-Dub e (BHD) syndrome, an autosomal dominant familial cancer, is associated with increased risk of kidney cancer. BHD syndrome is caused by loss-of-function mutations in the folliculin (FLCN) protein. To develop therapeutic approaches for renal cell carcinoma (RCC) in BHD syndrome, we adopted a strategy to identify tumor-selective growth inhibition in a RCC cell line with FLCN inactivation. The COMPARE algorithm was used to identify candidate anticancer drugs tested against the NCI-60 cell lines that showed preferential toxicity to low FLCN expressing cell lines. Fifteen compounds were selected and detailed growth inhibition (SRB) assays were done in paired BHD RCC cell lines (UOK257 derived from a patient with BHD). Selective sensitivity of FLCN-null over FLCN-wt UOK257 cells was observed in seven compounds. The most selective growth-inhibitory sensitivity was induced by mithramycin, which showed an approximately 10-fold difference in GI 50 values between FLCN-null (64.2 AE 7.9 nmol/L, n ¼ 3) and FLCN-wt UOK257 cells (634.3 AE 147.9 nmol/L, n ¼ 4). Differential ability to induce caspase 3/7 activity by mithramycin was also detected in a dose-dependent manner. Clonogenic survival studies showed mithramycin to be approximately 10-fold more cytotoxic to FLCN-null than FLCN-wt UOK257 cells (200 nmol/L). Following mithramycin exposure, UOK257-FLCN-null cells were mainly arrested and blocked in S and G 2 -M phases of the cell cycle and low dose of rapamycin (1 nmol/L) potentiated mithramycin sensitivity (1.5-fold in G 2 -M population and 2-fold in G 2 -M period time, 2xGI 50 , 48 hours). These results provide a basis for further evaluation of mithramycin as a potential therapeutic drug for RCC associated with BHD.

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Deficiency of FLCN in Mouse Kidney Led to Development of Polycystic Kidneys and Renal Neoplasia

Cited by 125 publications

References 33 publications

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

Tumor Biology and Prognostic Factors in Renal Cell Carcinoma

Therapeutic Targeting the Loss of the Birt-Hogg-Dubé Suppressor Gene

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