siRNA Knockdown of Ribonucleotide Reductase Inhibits Melanoma Cell Line Proliferation Alone or Synergistically with Temozolomide

Zuckerman, Jonathan E.; Hsueh, Teli; Koya, Richard C.; Davis, Mark E.; Ribas, Antoni

doi:10.1038/jid.2010.310

Cited by 40 publications

(31 citation statements)

References 22 publications

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“…In addition, compared with the controls of no treatment and siNC 50 nM, cells treated with siRRM2 (50 and 25 nM) displayed a remarkable and dose-dependent increase in S-phase populations; and the G2/M-phase population decreased significantly (Figures 4E and 4F). This was consistent with the S-phase cell-cycle arrest matched with the mechanism of action, and it was in line with the reported data 31, 45. Synthesis of RRM2 protein is regulated in a cell-cycle-dependent fashion.…”

Section: Resultssupporting

confidence: 92%

siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin

Zheng

Wang

Weng

et al. 2018

Molecular Therapy - Nucleic Acids

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Pancreatic cancer is currently one of the deadliest of the solid malignancies, whose incidence and death rates are increasing consistently during the past 30 years. Ribonucleotide reductase (RR) is a rate-limiting enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides, which are essential for DNA synthesis and replication. In this study, 23 small interfering RNAs (siRNAs) against RRM2, the second subunit of RR, were designed and screened, and one of them (termed siRRM2), with high potency and good RNase-resistant capability, was selected. Transfection of siRRM2 into PANC-1, a pancreatic cell line, dramatically repressed the formation of cell colonies by inducing remarkable cell-cycle arrest at S-phase. When combining with doxorubicin (DOX), siRRM2 improved the efficacy 4 times more than applying DOX alone, suggesting a synergistic effect of siRRM2 and DOX. Moreover, the combined application of siRRM2-loaded lipid nanoparticle and DOX significantly suppressed the tumor growth on the PANC-1 xenografted murine model. The inhibition efficiency revealed by tumor weight at the endpoint of the treatment reached more than 40%. Hence, siRRM2 effectively suppressed pancreatic tumor growth alone or synergistically with DOX. This study provides a feasible target gene, a drug-viable siRNA, and a promising therapeutic potential for the treatment of pancreatic cancer.

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Section: Resultssupporting

confidence: 92%

siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin

Zheng

Wang

Weng

et al. 2018

Molecular Therapy - Nucleic Acids

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“…1). This is consistent with previous studies showing that RRM2 inhibition can reduce melanoma cell proliferation regardless of BRAF mutation status (12, 13). Melanoma cell proliferation was further decreased when combined with the BRAFi PLX4720 (Fig.…”

Section: Discussionsupporting

confidence: 93%

“…This suggests RRM2 plays a significant role in melanoma cell proliferation and tumor progression. Indeed, knockdown of RRM2 inhibits melanoma cell proliferation (12, 13). However, whether inhibition of RRM2 can prolong the treatment effect of BRAFi has not been explored.…”

Section: Introductionmentioning

confidence: 99%

Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma

Fatkhutdinov

Sproesser

Krepler

et al. 2016

Molecular Cancer Research

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The majority of melanoma patients harbor mutations in the BRAF oncogene, thus making it a clinically relevant target. However, response to mutant BRAF inhibitors (BRAFi) is relatively short-lived with progression free survival of only 6–7 months. Previously, we reported high expression of ribonucleotide reductase M2 (RRM2), which is rate limiting for de novo dNTP synthesis, as a poor prognostic factor in mutant BRAF melanoma patients. In this study, the notion that targeting de novo dNTP synthesis through knockdown of RRM2 could prolong the response of melanoma cells to BRAFi was investigated. Knockdown of RRM2 in combination with the mutant BRAFi PLX4720 (an analog of the FDA-approved drug vemurafenib) inhibited melanoma cell proliferation to a greater extent than either treatment alone. This occurred in vitro in multiple mutant BRAF cell lines and in a novel patient-derived xenograft (PDX) model system. Mechanistically, the combination increased DNA damage accumulation, which correlated with a global decrease in DNA damage repair (DDR) gene expression and increased apoptotic markers. After discontinuing PLX4720 treatment, cells showed marked recurrence. However, knockdown of RRM2 attenuated this rebound growth both in vitro and in vivo, which correlated with maintenance of the senescence-associated cell cycle arrest.

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“…RRM2 contributes to malignant cellular phenotype in a range of human cancers and its overexpression plays a critical role in tumor invasion (13,14). A previous study showed that sequence-specific small interfering RNA (siRNA)-mediated inhibition of RRM2 effectively blocked the cell proliferation and induced G1/S phase cell cycle arrest in melanoma cell lines (15). However, the biological functions of RRM2 in gastric cancer remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Targeting ribonucleotide reductase M2 subunit by small interfering RNA exerts anti-oncogenic effects in gastric adenocarcinoma

et al. 2014

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Abstract. Ribonucleotide reductase M2 subunit (RRM2) is one of the two subunits of human ribonucleotide reductase which plays a critical role in tumor progression. The aim of the present study was to analyze its expression, clinical significance and biological functions in gastric adenocarcinoma. We observed the upregulation of RRM2 mRNA and protein in all nine gastric cancer cell lines examined. In paired primary gastric cancers, both mRNA and protein levels of RRM2 were significantly upregulated in tumors compared with the corresponding non-tumorous gastric tissues. RRM2 protein expression correlated with higher tumor grade, advanced T stage and poor disease-specific survival. RRM2 knockdown in gastric cancer cell lines AGS, MKN1 and MKN28 significantly suppressed cell proliferation, inhibited monolayer colony formation, reduced cell invasion and induced apoptosis. Downregulation of RRM2 suppressed xenograft formation in vivo. Collectively, these findings suggest that RRM2 plays a crucial role in gastric tumorigenesis and may serve as a potential prognostic marker and therapeutic target in gastric cancer.

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siRNA Knockdown of Ribonucleotide Reductase Inhibits Melanoma Cell Line Proliferation Alone or Synergistically with Temozolomide

Cited by 40 publications

References 22 publications

siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin

siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin

Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma

Targeting ribonucleotide reductase M2 subunit by small interfering RNA exerts anti-oncogenic effects in gastric adenocarcinoma

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