c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma

Gibney, Geoffrey T.; Aziz, Saadia A.; Camp, Robert L.; Conrad, Patricia J.; Schwartz, Brian; Chen, C. R.; Kelly, Wm. Kevin; Kluger, Harriet M.

doi:10.1093/annonc/mds463

Cited by 166 publications

(149 citation statements)

References 26 publications

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“…18,19 Given that c-Met is an upstream regulator of both these pathways, 6,10 we examined the potential effect of PL on c-Met protein expression in RCC cells. As demonstrated in Figure 1A, PL effectively depletes c-Met protein at low micromolar concentrations (>5 mM) in long-term cultured 786-O and patient-derived PNX0010 RCC cells.…”

Section: Pl Down-regulates C-met Expression In Rcc Cellsmentioning

confidence: 99%

“…Its only known ligand, hepatocyte growth factor (HGF), regulates cell growth, motility, migration, invasion, proliferation, and angiogenesis. [6][7][8] Dysregulation of c-Met signaling has been observed in both clear cell and non-clear cell renal cell carcinomas (RCCs). 7,9 The cMet signaling activates various intracellular effectors and pathways including PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, NF-kB, STAT3 and FAK.…”

Section: Introductionmentioning

confidence: 99%

“…7,9 The cMet signaling activates various intracellular effectors and pathways including PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, NF-kB, STAT3 and FAK. 6,10 The aberrant expression of c-Met often correlates with poor prognosis in multiple cancers including RCC. 6 In addition, c-Met plays a critical role in the development of resistance to targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

“…6,10 The aberrant expression of c-Met often correlates with poor prognosis in multiple cancers including RCC. 6 In addition, c-Met plays a critical role in the development of resistance to targeted therapies. 8,11 Discovery of c-Met and HGF overexpression in RCCs of all subtypes and the correlation between overexpression with worse outcomes reinforce the HGF/ c-Met pathway as a logical therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

“…8,11 Discovery of c-Met and HGF overexpression in RCCs of all subtypes and the correlation between overexpression with worse outcomes reinforce the HGF/ c-Met pathway as a logical therapeutic target. 6,7,9 Several approaches to target Met and its signaling have been developed including antagonists of HGF/c-Met and c-Met/effector interaction as well as inhibitors of c-Met activity. 7 Yet, amplification or expression of constitutively active c-Met forms may ultimately limit the use of such inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Piperlongumine and its analogs down-regulate expression of c-Met in renal cell carcinoma

Golovine

Makhov

Naito

et al. 2015

Cancer Biology & Therapy

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The c-Met protein, a transmembrane receptor tyrosine kinase, is the product of a proto-oncogene. Its only known ligand, hepatocyte growth factor (HGF), regulates cell growth, motility, migration, invasion, proliferation, and angiogenesis. The aberrant expression of c-Met is often associated with poor prognosis in multiple cancers, including renal cell carcinoma (RCC). Silencing or inactivation of c-Met leads to decreased viability of cancer cells, thereby making ablation of c-Met signaling an attractive concept for developing novel strategies for the treatment of renal tumors. Naturally-occurring products or substances are the most consistent source of drug development. As such, we investigated the functional impact of piperlongumine (PL), a naturally occurring alkaloid present in the Long pepper (Piper longum) on c-Met expression in RCC cells and demonstrated that PL and its analogs rapidly reduce c-Met protein and RNA levels in RCC cells via ROS-dependent mechanism. PL-mediated c-Met depletion coincided with the inhibition of downstream c-Met signaling; namely Erk/MAPK, STAT3, NF-kB and Akt/mTOR. As such, PL and PL analogs hold promise as potential therapeutic agents for the treatment of metastatic RCC and the prevention of postoperative RCC recurrence.

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Section: Pl Down-regulates C-met Expression In Rcc Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Piperlongumine and its analogs down-regulate expression of c-Met in renal cell carcinoma

Golovine

Makhov

Naito

et al. 2015

Cancer Biology & Therapy

View full text Add to dashboard Cite

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Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma

Hakimi

Ostrovnaya

Jacobsen

et al. 2015

Cancer

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Background The exonic single nucleotide variant rs11762213 located in the MET oncogene has recently been identified as a prognostic marker in clear cell renal cell carcinoma (ccRCC). We validated this finding using the Cancer Genome Atlas cohort and explored the biologic implications. Methods Genotype status for rs11762213 was available for 272 patients. Paired tumor-normal data, genomic data and clinical information were acquired from ccRCC TCGA datasets. Cancer specific survival (CSS) was analyzed using the competing risk method and Cox proportional hazard regression was used for analysis of time to recurrence (TTR). Multivariate competing risk models were fitted to adjust for the validated Mayo Clinic Stage, Size, Grade and Necrosis (SSIGN) score. Results The variant allele of rs11762213 was detected in 10.3% of the cohort. After adjusting for SSIGN score, the risk allele remained a significant predictor for adverse CSS (p<0.0001; Odds Ratio [OR] 3.88, 95% confidence interval [CI] 1.99-7.56) and for TTR (p=0.003; OR 2.97; 95% CI 1.43-6.2). Mapping of rs11762213 to regulatory regions within the genome suggests that it may impact a DNA enhancer region. RNA and protein sequencing data for MET did not reveal differences in steady-state expression when stratified by risk allele. Conclusions The exonic MET variant rs11762213 is an independent predictor of adverse CSS and TTR in ccRCC and should be integrated into clinical practice for prognostic stratification. Genomic analysis suggests that the SNP may affect an enhancer region located in the coding region of MET. Further biological mechanistic interrogation is currently underway.

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In Vitro Antitumor Effects of AHR Ligands Aminoflavone (AFP 464) and Benzothiazole (5F 203) in Human Renal Carcinoma Cells

Luzzani

Callero

Kuruppu

et al. 2017

J of Cellular Biochemistry

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We investigated activity and mechanism of action of two AhR ligand antitumor agents, AFP 464 and 5F 203 on human renal cancer cells, specifically examining their effects on cell cycle progression, apoptosis and migration. TK-10, SN12C, Caki-1 and ACHN human renal cancer cell lines were treated with AFP 464 and 5F 203. We evaluated cytotoxicity by MTS assays, cell cycle arrest and apoptosis by flow cytometry and corroborated a mechanism of action involving AhR signal transduction activation. Changes in migration properties by wound healing assays were investigated: 5F 203-sensitive cells show decreased migration after treatment, therefore we measured c-Met phosphorylation by Western blot in these cells. Both compounds caused cell cycle arrest and apoptosis in sensitive cell lines TK-10, SN12C and Caki-1 cell lines. 5F 203 induced a decrease in cell viability which was more remarkable marked than AFP 464. This cytotoxicity was reduced after treatment with the AhR inhibitor α-NF for both compounds indicating Ahr AhR signaling activation plays a role in the mechanism of action. 5F 203 is sequestered by TK-10 cells and induces CYP1A1 expression; 5F 203 only potently inhibited migration of TK-10, Caki-1 and SN12C cells, and inhibited c-Met receptor phosphorylation in TK-10 cells. AhR ligand antitumor agents AFP 464 and 5F 203 represent potential new candidates for the treatment of renal cancer. 5F 203 only inhibited migration of sensitive cells and c-Met receptor phosphorylation in TK-10 cells. c-Met receptor signal transduction is important in migration and metastasis. Therefore we consider that 5F 203 offers potential for the treatment of metastatic renal carcinoma.

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c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma

Abstract: c-Met is associated with poor pathologic features and prognosis in RCC. c-Met inhibition demonstrates in vitro activity against clear cell RCC. Further study of ARQ 197 with appropriate biomarker studies in RCC is warranted.

Cited by 166 publications

References 26 publications

Piperlongumine and its analogs down-regulate expression of c-Met in renal cell carcinoma

Piperlongumine and its analogs down-regulate expression of c-Met in renal cell carcinoma

Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma

In Vitro Antitumor Effects of AHR Ligands Aminoflavone (AFP 464) and Benzothiazole (5F 203) in Human Renal Carcinoma Cells

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