Molecule Information

General Information of the Molecule (ID: Mol00245)

• Name: Bcl-2-associated agonist of cell death (BAD) ,Homo sapiens
• Synonyms: BAD; Bcl-2-binding component 6; Bcl-2-like protein 8; Bcl2-L-8; Bcl-xL/Bcl-2-associated death promoter; Bcl2 antagonist of cell death; BBC6; BCL2L8
• Molecule Type: Protein
• Gene Name: BAD
• Gene ID: 572
• Location: chr11:64269830-64284704[-]
• Sequence:
  MFQIPEFEPSEQEDSSSAERGLGPSPAGDGPSGSGKHHRQAPGLLWDASHQQEQPTSSSH
  HGGAGAVEIRSRHSSYPAGTEDDEGMGEEPSPFRGRSRSAPPNLWAAQRYGRELRRMSDE
  FVDSFKKGLPRPKSAGTATQMRQSSSWTRVFQSWWDRNLGRGSSAPSQ
• Function: Promotes cell death. Successfully competes for the binding to Bcl-X(L), Bcl-2 and Bcl-W, thereby affecting the level of heterodimerization of these proteins with BAX. Can reverse the death repressor activity of Bcl-X(L), but not that of Bcl-2 (By similarity). Appears to act as a link between growth factor receptor signaling and the apoptotic pathways.
• Uniprot ID: BAD_HUMAN
• Ensembl ID: ENSG00000002330
• HGNC ID: HGNC:936

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

Type(s) of Resistant Mechanism of This Molecule

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Carboplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Pituitary adenoma [1]

• Resistant Disease: Pituitary adenoma [ICD-11: 2F37.1]
• Resistant Drug: Carboplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pituitary tumour stem-like cells; Pituitary; Homo sapiens (Human); N.A.
• In Vivo Model: NOD/SCID mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 proliferation assay
• Mechanism Description: Stem cells are generally known to preferentially express antiapoptotic genes, such as BCL-2, cIAP1, NAIP, and XIAP.The expression levels of these antiapoptotic genes in PASC1 were one- to sixfolds higher than those in its daughter cells.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Prostate cancer [2]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-17-92 cluster plays a crucial role in cell growth of the DU145 prostate cancer cells due to regulation of cellular apoptosis-related and proliferation-related proteins, and causes chemo-resistance to cisplatin via activating AkT signaling together with upregulating ERCC1 also contributed to development of cisplatin-resistance.

Disease Class: Prostatic intraepithelial neoplasia [3]

• Resistant Disease: Prostatic intraepithelial neoplasia [ICD-11: 2C82.2]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC-3 cells; Bone; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Forced expression of the PCPH protein or, in particular, of the mt-PCPH oncoprotein increased the levels of phosphorylated PKCalpha concurrently with those of Ser70-phosphorylated and total Bcl-2 protein, thus promoting cisplatin resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hepatocellular carcinoma [4]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Sensitive Drug: Cisplatin
• 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 proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer bone metastasis [5]

• Resistant Disease: Breast cancer bone metastasis [ICD-11: 2E03.1]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• 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: RT-PCR
• Experiment for Drug Resistance: Flow cytometric
• Mechanism Description: Interleukin-6 (IL-6), a pro-inflammatory cytokine produced in the tumor microenvironment by stromal cells, fibroblasts, and cancer cells. Binding of IL-6 to its receptor IL-6R on the cell membrane activates Janus Kinase 2 (JAK2) kinases. Activated JAK2 mediates phosphorylation, dimerization, and nuclear translocation of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 signaling mediates the expression of various genes, including p53, Bcl-2, MRP1, and ABCG2. Bcl-2 and p53 are associated with regulation of apoptosis while overexpression of drug transporters MRP1, ABCG2 has been shown to mediate efflux of drugs from cancer cells, thus decreasing intracellular drug concentration leading to drug-resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Lung adenocarcinoma [6]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical 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: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Tunel assay
• Mechanism Description: Long noncoding RNA CCAT1 acts as an oncogene and promotes chemoresistance in docetaxel-resistant lung adenocarcinoma cells.the sponging of let-7c by CCAT1 released Bcl-xl (a let-7c target), thereby promoting the acquisition of chemoresistance and epithelial-to-mesenchymal transition phenotypes in docetaxel-resistant LAD cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [7]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Caspase-3 signaling pathway; Activation; hsa04210
• Cell Pathway Regulation: Sorafenib tolerance; Activation; hsa00983
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Ectopic Let-7c expression could increase the sensitivity of docetaxel-resistant LAD cells to chemotherapeutic agents or irradiation and reverse their EMT phenotype by targeting Bcl-xL.

Etoposide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Pituitary adenoma [1]

• Resistant Disease: Pituitary adenoma [ICD-11: 2F37.1]
• Resistant Drug: Etoposide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pituitary tumour stem-like cells; Pituitary; Homo sapiens (Human); N.A.
• In Vivo Model: NOD/SCID mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 proliferation assay
• Mechanism Description: Stem cells are generally known to preferentially express antiapoptotic genes, such as BCL-2, cIAP1, NAIP, and XIAP.The expression levels of these antiapoptotic genes in PASC1 were one- to sixfolds higher than those in its daughter cells.

Fluorouracil

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hepatocellular carcinoma [4], [8]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Sensitive Drug: Fluorouracil
• 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 proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; MTT assay
• Mechanism Description: Let-7b increased 5 FU sensitivity by repressing Bcl xl expression in HCC cells. And miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Liver cancer [ICD-11: 2C12]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Liver
• The Specified Disease: Liver cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.27E-01; Fold-change: -1.33E-01; Z-score: -2.65E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 6.49E-13; Fold-change: 4.05E-01; Z-score: 7.60E-01
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 4.71E-01; Fold-change: -2.13E-01; Z-score: -4.35E-01

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: 8.54E-01; Fold-change: -1.17E-01; Z-score: -2.02E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 8.20E-01; Fold-change: -5.20E-02; Z-score: -9.68E-02

Prostate cancer [ICD-11: 2C82]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Prostate
• The Specified Disease: Prostate cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.50E-03; Fold-change: -4.44E-01; Z-score: -7.28E-01

Pituitary cancer [ICD-11: 2F37]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Pituitary
• The Specified Disease: Pituitary cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.09E-03; Fold-change: 6.13E-01; Z-score: 1.04E+00
• The Studied Tissue: Pituitary
• The Specified Disease: Pituitary gonadotrope tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.64E-04; Fold-change: 8.24E-01; Z-score: 1.71E+00

References

• Ref 1: Isolation of tumour stem-like cells from benign tumours .Br J Cancer. 2009 Jul 21;101(2):303-11. doi: 10.1038/sj.bjc.6605142. Epub 2009 Jun 30. 10.1038/sj.bjc.6605142
• Ref 2: miR-17-92 plays an oncogenic role and conveys chemo-resistance to cisplatin in human prostate cancer cells. Int J Oncol. 2016 Apr;48(4):1737-48. doi: 10.3892/ijo.2016.3392. Epub 2016 Feb 15.
• Ref 3: PCPH/ENTPD5 expression confers to prostate cancer cells resistance against cisplatin-induced apoptosis through protein kinase Calpha-mediated Bcl-2 stabilization .Cancer Res. 2009 Jan 1;69(1):102-10. doi: 10.1158/0008-5472.CAN-08-2922. 10.1158/0008-5472.CAN-08-2922
• Ref 4: MicroRNA 133a and microRNA 326 co contribute to hepatocellular carcinoma 5 fluorouracil and cisplatin sensitivity by directly targeting B cell lymphoma extra large. Mol Med Rep. 2015 Oct;12(4):6235-40. doi: 10.3892/mmr.2015.4134. Epub 2015 Jul 29.
• Ref 5: Bone interface modulates drug resistance in breast cancer bone metastasis .Colloids Surf B Biointerfaces. 2020 Nov;195:111224. doi: 10.1016/j.colsurfb.2020.111224. Epub 2020 Jun 26. 10.1016/j.colsurfb.2020.111224
• Ref 6: Long noncoding RNA CCAT1 acts as an oncogene and promotes chemoresistance in docetaxel-resistant lung adenocarcinoma cells. Oncotarget. 2016 Sep 20;7(38):62474-62489. doi: 10.18632/oncotarget.11518.
• Ref 7: Let-7c governs the acquisition of chemo- or radioresistance and epithelial-to-mesenchymal transition phenotypes in docetaxel-resistant lung adenocarcinoma. Mol Cancer Res. 2013 Jul;11(7):699-713. doi: 10.1158/1541-7786.MCR-13-0019-T. Epub 2013 Apr 5.
• Ref 8: Let-7b binding site polymorphism in the B-cell lymphoma-extra large 3'UTR is associated with fluorouracil resistance of hepatocellular carcinoma. Mol Med Rep. 2015 Jan;11(1):677-81. doi: 10.3892/mmr.2014.2692. Epub 2014 Oct 17.