Kidney-Targeted Birt-Hogg-Dube Gene Inactivation in a Mouse Model: Erk1/2 and Akt-mTOR Activation, Cell Hyperproliferation, and Polycystic Kidneys

M, Baba; Furihata, Mutsuo; Hong, Seung Beom; Tessarollo, Lino; Haines, Diana C.; Southon, Eileen; Patel, Vishal; Igarashi, Peter; Alvord, W. Gregory; Leighty, Robert M.; Yao, Masahiro; Bernardo, Marcelino; Ileva, Lilia; Choyke, Peter L.; Warren, Michelle B.; Zbar, Berton; Linehan, W. Marston; Schmidt, Laura S.

doi:10.1093/jnci/djm288

Cited by 216 publications

(282 citation statements)

References 45 publications

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“…Aberrant mTOR signaling has been reported to be associated with FLCN/Flcn inactivation in human cell lines (13) and in transgenic mice (14,16). Hence, we proceeded to investigate whether inhibition of the mTOR pathway by rapamycin influenced the differential mithramycin sensitivity found in UOK cells with/without FLCN expression.…”

Section: Comparison Of Mithramycin Alone or In Combination Of Rapamycmentioning

confidence: 99%

“…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%

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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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Section: Comparison Of Mithramycin Alone or In Combination Of Rapamycmentioning

confidence: 99%

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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“…It is caused by germline mutations in the folliculin (FLCN) gene (Chr17p11), described to act as a canonical tumour suppressor gene (TSG). 1 Although the function of FLCN is still unknown, it has been shown to act upstream of mammalian target of rapamycin complex 1 (mTORC1) [2][3][4][5] and a role in energy/ nutrient-sensing signalling pathways has been suggested. 6 The association of benign cutaneous lesions and increased cancer risk is also a feature of Cowden Syndrome (CS), an autosomal dominant disease caused by PTEN (phosphatase and tensin homologue deleted on Chromosome 10) mutations and mainly characterised by macrocephaly, mucocutaneous lesions and cancer predisposition.…”

Section: Introductionmentioning

confidence: 99%

Where Birt–Hogg–Dubé meets Cowden Syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours

et al. 2013

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Birt-Hogg-Dubè (BHD) is an autosomal dominant syndrome characterised by skin fibrofolliculomas, lung cysts, spontaneous pneumothorax and renal cancer. The association of benign cutaneous lesions and increased cancer risk is also a feature of Cowden Syndrome (CS), an autosomal dominant disease caused by PTEN mutations. BHD and CS patients may develop oncocytomas, rare neoplasias that are phenotypically characterised by a prominent mitochondrial hyperplasia. We here describe the genetic analysis of a parotid and a thyroid oncocytoma, developed by a BHD and a CS patient, respectively. The BHD lesion was shown to maintain the wild-type allele of FLCN, while losing one PTEN allele. On the other hand, a double heterozygosity for the same two genes was found to be the only detectable tumorigenic hit in the CS oncocytoma. Both conditions occurred in a context of high chromosomal stability, as highlighted by comparative genomic hybridisation analysis. We conclude that, similarly to PTEN, FLCN may not always follow the classical Two Hits model of tumorigenesis and may hence belong to a class of non-canonical tumour suppressor genes. We hence introduce a role of PTEN/FLCN double heterozygosity in syndromic oncocytic tumorigenesis, suggesting this to be an alternative determinant to pathogenic mitochondrial DNA mutations, which are instead the genetic hallmark of sporadic oncocytic tumours.

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“…2 Currently, no treatment for ADPKD is available, and most patients eventually require lifelong dialysis or kidney transplantation. We 3,4 and others [5][6][7][8][9][10][11] have demonstrated that the mammalian target of rapamycin (mTOR) pathway is hyperactivated in PKD rodent models and human ADPKD. Furthermore, treatment of PKD rodent models with mTOR inhibitors, such as rapamycin, greatly improves the cystic phenotype.…”

mentioning

confidence: 99%

“…Furthermore, treatment of PKD rodent models with mTOR inhibitors, such as rapamycin, greatly improves the cystic phenotype. [5][6][7][8][9][10][11] Because mTOR inhibitors have already been in clinical use as immunosuppressant drugs, these studies rapidly led to several clinical trials to determine whether they are effective in patients with APDKD. [12][13][14] Unfortunately, although not yet fully conclusive, the results of these trials have been largely disappointing.…”

mentioning

confidence: 99%

Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease

Shillingford

Leamon

Vlahov

et al. 2012

Journal of the American Society of Nephrology

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Activation of the mammalian target of rapamycin (mTOR) signaling pathway is aberrant in autosomaldominant polycystic kidney disease (ADPKD). The mTOR inhibitors, such as rapamycin, ameliorate PKD in rodent models, but clinical trials have not shown benefit, possibly as a result of low tissue concentrations of rapamycin at clinically tolerable doses. To overcome this limitation, we synthesized a folate-conjugated form of rapamycin (FC-rapa) that is taken up by folate receptor-mediated endocytosis and cleaved intracellularly to reconstitute the active drug. We found that renal cyst-lining cells highly express the folate receptor in ADPKD and mouse models. In vitro, FC-rapa inhibited mTOR activity in a dose-and folate receptor-dependent manner. Treatment of a PKD mouse model with FC-rapa inhibited mTOR in the target tissue, strongly attenuated proliferation and growth of renal cysts and preserved renal function. Furthermore, FC-rapa inhibited mTOR activity in the kidney but not in other organs. In summary, these results suggest that targeting the kidney using FC-rapa may overcome the significant side effects and lack of renal efficacy observed in clinical trials with mTOR inhibitors in ADPKD.

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Kidney-Targeted Birt-Hogg-Dube Gene Inactivation in a Mouse Model: Erk1/2 and Akt-mTOR Activation, Cell Hyperproliferation, and Polycystic Kidneys

Abstract: Homozygous loss of BHD may initiate renal tumorigenesis in the mouse. The conditional BHD knockout mouse may be a useful research model for dissecting multistep kidney carcinogenesis, and rapamycin may be considered as a potential treatment for Birt-Hogg-Dubé syndrome.

Cited by 216 publications

References 45 publications

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

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

Where Birt–Hogg–Dubé meets Cowden Syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours

Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease

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