Inhibiting RRM2 to enhance the anticancer activity of chemotherapy

Zhan, Yaqiong; Jiang, Lushun; Jin, Xuehang; Ying, Shuaibing; Wu, Zhe; Wang, Li; Yu, Wei; Tong, Jijun; Zhang, Li; Lou, Yan; Qiu, Yunqing

doi:10.1016/j.biopha.2020.110996

Cited by 59 publications

(52 citation statements)

References 89 publications

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“…Its oncogenic effects in GC progression have been identified as previously reported [35][36][37]. Importantly, research has indicated that inhibiting RRM2 may be a potential therapeutic strategy to overcome the resistance of chemotherapy [38].…”

Section: Discussionmentioning

confidence: 99%

Knockdown of lncRNA SNHG4 suppresses gastric cancer cell proliferation and metastasis by targeting miR-204-5p

Cheng¹,

Zhang²,

Zhu³

et al. 2021

neo

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Long non-coding RNAs (lncRNAs) have been identified as critical regulators in gastric cancer (GC) progression. However, whether lncRNA small nucleolar host gene 4 (SNHG4) functions in GC development remains unknown. In this study, the bio-functional role of SNHG4 and its potential mechanism on GC progression were systematically dissected. To investigate the role of SNHG4 in GC, we silenced SNHG4 using short hairpin RNAs (shRNAs) to perform loss-of-function assays. The results showed that SNHG4 expression in GC cells was at a higher level compared to normal gastric mucosal epithelial cells. Knockdown of SNHG4 dramatically suppressed proliferation, migration and invasion, and blocked cell cycle progression of GC cells. Moreover, knockdown of SNHG4 upregulated microRNA-204-5p (miR-204-5p) expression, whereas downregulated ribonucleotide reductase subunit M2 (RRM2) expression in GC cells. Dua l-luciferase reporter assay results showed that miR-204-5p was a direct target of SN HG4. Additionally, knockdown of SHNG4 suppressed GC tumorigenesis in xenograft mouse models. Taken together, these data demonstrated that knockdown of SNHG4 suppressed GC development by targeting miR-204-5p.

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Section: Discussionmentioning

confidence: 99%

Knockdown of lncRNA SNHG4 suppresses gastric cancer cell proliferation and metastasis by targeting miR-204-5p

Cheng¹,

Zhang²,

Zhu³

et al. 2021

neo

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“…Ribonucleotide reductase subunit M2 (RRM2) is a ribonucleotide reductase (RNR) subunit that catalyzes the synthesis of deoxyribonucleotides. [ 12 ] RRM2 overexpression has been reported in many types of cancer and has been implicated in tumor progression. [ 13 ] Additionally, microRNA (miR)‐99a‐3p targeting RRM2 mRNA is often downregulated in sunitinib‐resistant RCC cells, [ 14 ] suggesting that RRM2 may be overexpressed in sunitinib‐resistant RCC cells.…”

Section: Introductionmentioning

confidence: 99%

RRM2 Regulates Sensitivity to Sunitinib and PD‐1 Blockade in Renal Cancer by Stabilizing ANXA1 and Activating the AKT Pathway

Wang

Zhang

et al. 2021

Advanced Science

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Renal cell carcinoma (RCC) is a malignant tumor of the kidneys.Approximately 70% of RCC cases are clear cell renal cell carcinoma with von Hippel-Lindau (VHL) gene mutation and activation of the vascular endothelial growth factor (VEGF) pathway. Tyrosine kinase inhibitors (TKIs) targeting VEGF have emerged as promising agents for RCC treatment. Apart from primary resistance, acquired resistance to TKIs after initial tumor regression is common in RCC. Recently, immune checkpoint inhibition, including PD-1/PD-L1 blockade, alone or in combination with TKIs has improved the overall survival of patients with RCC. Ribonucleotide reductase subunit M2 (RRM2) has been reported in many types of cancer and has been implicated in tumor progression. However, the role of RRM2 in TKIs resistance in RCC remains unclear. In this study, the authors have demonstrated that RRM2 is upregulated in sunitinib-resistant RCC cells and patient tissues. They also find that RRM2 stabilizes ANXA1 and activates the AKT pathway independent of its ribonucleotide reductase activity, promoting sunitinib resistance in RCC. Moreover, RRM2 regulated antitumor immune responses, and knockdown of RRM2 enhance the anti-tumor efficiency of PD-1 blockade in renal cancer. Collectively, these results suggest that aberrantly expressed RRM2 may be a promising therapeutic target for RCC.

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“…It has been reported that RRM2 plays an essential role in cancer cell proliferation and the development of resistance to GEM in pancreatic tumor cells [ 11 , 12 ]. Studies have demonstrated that overexpression of RRM2 enhanced DNA damage repair and replication, leading to decreased chemosensitivity of GEM [ 13 ]. In addition, clinical data demonstrated that patients who have elevated RRM2 expression had less response to gemcitabine-based chemotherapy, and high expression of RRM2 in pancreatic cancer is associated with a poor prognosis [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

M1 Macrophage-Derived Exosomes Loaded with Gemcitabine and Deferasirox against Chemoresistant Pancreatic Cancer

et al. 2021

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Pancreatic cancer is a malignant disease with high mortality and poor prognosis due to lack of early diagnosis and low treatment efficiency after diagnosis. Although Gemcitabine (GEM) is used as the first-line chemotherapeutic drug, chemoresistance is still the major problem that limits its therapeutic efficacy. Here in this study, we developed a specific M1 macrophage-derived exosome (M1Exo)-based drug delivery system against GEM resistance in pancreatic cancer. In addition to GEM, Deferasirox (DFX) was also loaded into drug carrier, M1Exo, in order to inhibit ribonucleotide reductase regulatory subunit M2 (RRM2) expression via depleting iron, and thus increase chemosensitivity of GEM. The M1Exo nanoformulations combining both GEM and DFX significantly enhanced the therapeutic efficacy on the GEM-resistant PANC-1/GEM cells and 3D tumor spheroids by inhibiting cancer cell proliferation, cell attachment and migration, and chemoresistance to GEM. These data demonstrated that M1Exo loaded with GEM and DFX offered an efficient therapeutic strategy for drug-resistant pancreatic cancer.

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Inhibiting RRM2 to enhance the anticancer activity of chemotherapy

Cited by 59 publications

References 89 publications

Knockdown of lncRNA SNHG4 suppresses gastric cancer cell proliferation and metastasis by targeting miR-204-5p

Knockdown of lncRNA SNHG4 suppresses gastric cancer cell proliferation and metastasis by targeting miR-204-5p

RRM2 Regulates Sensitivity to Sunitinib and PD‐1 Blockade in Renal Cancer by Stabilizing ANXA1 and Activating the AKT Pathway

M1 Macrophage-Derived Exosomes Loaded with Gemcitabine and Deferasirox against Chemoresistant Pancreatic Cancer

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