Molecule Information

General Information of the Molecule (ID: Mol00605)

• Name: Ribonucleoside-diphosphate reductase subunit M2 (RRM2) ,Homo sapiens
• Synonyms: Ribonucleotide reductase small chain; Ribonucleotide reductase small subunit; RR2
• Molecule Type: Protein
• Gene Name: RRM2
• Gene ID: 6241
• Location: chr2:10120698-10211725[+]
• Sequence:
  MLSLRVPLAPITDPQQLQLSPLKGLSLVDKENTPPALSGTRVLASKTARRIFQEPTEPKT
  KAAAPGVEDEPLLRENPRRFVIFPIEYHDIWQMYKKAEASFWTAEEVDLSKDIQHWESLK
  PEERYFISHVLAFFAASDGIVNENLVERFSQEVQITEARCFYGFQIAMENIHSEMYSLLI
  DTYIKDPKEREFLFNAIETMPCVKKKADWALRWIGDKEATYGERVVAFAAVEGIFFSGSF
  ASIFWLKKRGLMPGLTFSNELISRDEGLHCDFACLMFKHLVHKPSEERVREIIINAVRIE
  QEFLTEALPVKLIGMNCTLMKQYIEFVADRLMLELGFSKVFRVENPFDFMENISLEGKTN
  FFEKRVGEYQRMGVMSSPTENSFTLDADF
• Function: Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. Inhibits Wnt signaling.
• Uniprot ID: RIR2_HUMAN
• Ensembl ID: ENSG00000171848
• HGNC ID: HGNC:10452

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Gemcitabine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Pancreatic cancer [1]

• Sensitive Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Sensitive Drug: Gemcitabine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-20a-5p inhibits protein expression of RRM2 and reverses gemcitabine resistance.

Disease Class: KRAS mutant breast cancer [2]

• Sensitive Disease: KRAS mutant breast cancer [ICD-11: 2C60.10]
• Sensitive Drug: Gemcitabine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: MEK/ERK /PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Let-7b repletion selectively sensitized kRAS mutant tumor cells to the cytotoxicity of paclitaxel and gemcitabine. Transfection of let-7b mimic downregulated the expression of mutant but not wild-type kRAS. Combination of let-7b mimic with paclitaxel or gemcitabine diminished MEk/ERk and PI3k/AkT signaling concurrently, triggered the onset of apoptosis, and reverted the epithelial-mesenchymal transition in kRAS mutant tumor cells. In addition, let-7b repletion downregulated the expression of beta-tubulin III and ribonucleotide reductase subunit M2, two proteins known to mediate tumor resistance to paclitaxel and gemcitabine, respectively. Let-7 may represent a new class of chemosensitizer for the treatment of kRAS mutant tumors.

Disease Class: kRAS mutant non-small cell lung cancer [2]

• Sensitive Disease: kRAS mutant non-small cell lung cancer [ICD-11: 2C25.9]
• Sensitive Drug: Gemcitabine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: MEK/ERK /PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Let-7b repletion selectively sensitized kRAS mutant tumor cells to the cytotoxicity of paclitaxel and gemcitabine. Transfection of let-7b mimic downregulated the expression of mutant but not wild-type kRAS. Combination of let-7b mimic with paclitaxel or gemcitabine diminished MEk/ERk and PI3k/AkT signaling concurrently, triggered the onset of apoptosis, and reverted the epithelial-mesenchymal transition in kRAS mutant tumor cells. In addition, let-7b repletion downregulated the expression of beta-tubulin III and ribonucleotide reductase subunit M2, two proteins known to mediate tumor resistance to paclitaxel and gemcitabine, respectively. Let-7 may represent a new class of chemosensitizer for the treatment of kRAS mutant tumors.

Disease Class: KRAS mutant pancreatic ductal adenocarcinoma [2]

• Sensitive Disease: KRAS mutant pancreatic ductal adenocarcinoma [ICD-11: 2C10.5]
• Sensitive Drug: Gemcitabine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: MEK/ERK /PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Let-7b repletion selectively sensitized kRAS mutant tumor cells to the cytotoxicity of paclitaxel and gemcitabine. Transfection of let-7b mimic downregulated the expression of mutant but not wild-type kRAS. Combination of let-7b mimic with paclitaxel or gemcitabine diminished MEk/ERk and PI3k/AkT signaling concurrently, triggered the onset of apoptosis, and reverted the epithelial-mesenchymal transition in kRAS mutant tumor cells. In addition, let-7b repletion downregulated the expression of beta-tubulin III and ribonucleotide reductase subunit M2, two proteins known to mediate tumor resistance to paclitaxel and gemcitabine, respectively. Let-7 may represent a new class of chemosensitizer for the treatment of kRAS mutant tumors.

Disease Class: Pancreatic cancer [3]

• Sensitive Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Sensitive Drug: Gemcitabine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Suit2 cells; Pancreas; Homo sapiens (Human); CVCL_3172
• In Vitro Model: SUIT2-007 cells; Pancreas; Homo sapiens (Human); CVCL_B279
• In Vitro Model: SUIT2-028 cells; Pancreas; Homo sapiens (Human); CVCL_B282
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Transwell assay
• Mechanism Description: The induction of the miR-211 expression in the cells increased the sensitivity to gemcitabine and reduced the expression of its target ribonucleotide reductase subunit 2 (RRM2).

Paclitaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: KRAS mutant breast cancer [2]

• Sensitive Disease: KRAS mutant breast cancer [ICD-11: 2C60.10]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: MEK/ERK /PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Let-7b repletion selectively sensitized kRAS mutant tumor cells to the cytotoxicity of paclitaxel and gemcitabine. Transfection of let-7b mimic downregulated the expression of mutant but not wild-type kRAS. Combination of let-7b mimic with paclitaxel or gemcitabine diminished MEk/ERk and PI3k/AkT signaling concurrently, triggered the onset of apoptosis, and reverted the epithelial-mesenchymal transition in kRAS mutant tumor cells. In addition, let-7b repletion downregulated the expression of beta-tubulin III and ribonucleotide reductase subunit M2, two proteins known to mediate tumor resistance to paclitaxel and gemcitabine, respectively. Let-7 may represent a new class of chemosensitizer for the treatment of kRAS mutant tumors.

Disease Class: kRAS mutant non-small cell lung cancer [2]

• Sensitive Disease: kRAS mutant non-small cell lung cancer [ICD-11: 2C25.9]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: MEK/ERK /PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Let-7b repletion selectively sensitized kRAS mutant tumor cells to the cytotoxicity of paclitaxel and gemcitabine. Transfection of let-7b mimic downregulated the expression of mutant but not wild-type kRAS. Combination of let-7b mimic with paclitaxel or gemcitabine diminished MEk/ERk and PI3k/AkT signaling concurrently, triggered the onset of apoptosis, and reverted the epithelial-mesenchymal transition in kRAS mutant tumor cells. In addition, let-7b repletion downregulated the expression of beta-tubulin III and ribonucleotide reductase subunit M2, two proteins known to mediate tumor resistance to paclitaxel and gemcitabine, respectively. Let-7 may represent a new class of chemosensitizer for the treatment of kRAS mutant tumors.

Disease Class: KRAS mutant pancreatic ductal adenocarcinoma [2]

• Sensitive Disease: KRAS mutant pancreatic ductal adenocarcinoma [ICD-11: 2C10.5]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: MEK/ERK /PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Let-7b repletion selectively sensitized kRAS mutant tumor cells to the cytotoxicity of paclitaxel and gemcitabine. Transfection of let-7b mimic downregulated the expression of mutant but not wild-type kRAS. Combination of let-7b mimic with paclitaxel or gemcitabine diminished MEk/ERk and PI3k/AkT signaling concurrently, triggered the onset of apoptosis, and reverted the epithelial-mesenchymal transition in kRAS mutant tumor cells. In addition, let-7b repletion downregulated the expression of beta-tubulin III and ribonucleotide reductase subunit M2, two proteins known to mediate tumor resistance to paclitaxel and gemcitabine, respectively. Let-7 may represent a new class of chemosensitizer for the treatment of kRAS mutant tumors.

Tamoxifen

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [4]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Tamoxifen
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Increased expression of ribonucleotide reductase subunit M2 (RRM2) was found to be significantly linked to poor survival in all breast cancer patients as well as in ER-positive patients resistant to TAM. Azacytidine treatment in the TAMR cell line results in reduced proliferation and consequently resensitizes cells to TAM treatment. RRM2 is one of the isoforms of the enzyme ribonucleotide reductase, which is involved in the conversion of deoxyribonucleotides from their corresponding ribonucleotides that are required for DNA synthesis. A DNA methyl transferase inhibitor azacytidine has been shown to inhibit the expression of RRM2. Down-regulation of RRM2 by siRNA-mediated approaches significantly reduces TAMR cell growth, invasion and motility. RRM2 inhibition also leads to decreased expression of DNA repair enzymes and elevated expression of pro-apoptotic proteins such as BIM and BAX leading to apoptosis.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Pancreatic cancer [ICD-11: 2C10]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Pancreas
• The Specified Disease: Pancreatic cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.66E-04; Fold-change: 2.66E+00; Z-score: 1.68E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 6.56E-10; Fold-change: 1.69E+00; Z-score: 1.19E+00

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.24E-102; Fold-change: 3.27E+00; Z-score: 3.29E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 7.12E-81; Fold-change: 3.60E+00; Z-score: 4.10E+00

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.61E-249; Fold-change: 3.92E+00; Z-score: 4.82E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.60E-16; Fold-change: 2.75E+00; Z-score: 1.98E+00

References

• Ref 1: MiR-20a-5p regulates gemcitabine chemosensitivity by targeting RRM2 in pancreatic cancer cells and serves as a predictor for gemcitabine-based chemotherapy. Biosci Rep. 2019 May 7;39(5):BSR20181374. doi: 10.1042/BSR20181374. Print 2019 May 31.
• Ref 2: Let-7 Sensitizes KRAS Mutant Tumor Cells to Chemotherapy. PLoS One. 2015 May 6;10(5):e0126653. doi: 10.1371/journal.pone.0126653. eCollection 2015.
• Ref 3: miR-211 modulates gemcitabine activity through downregulation of ribonucleotide reductase and inhibits the invasive behavior of pancreatic cancer cells. Nucleosides Nucleotides Nucleic Acids. 2014;33(4-6):384-93. doi: 10.1080/15257770.2014.891741.
• Ref 4: Metabolic reprograming confers tamoxifen resistance in breast cancer. Chem Biol Interact. 2021 Sep 25;347:109602. doi: 10.1016/j.cbi.2021.109602. Epub 2021 Jul 28.