Molecule Information

General Information of the Molecule (ID: Mol04075)

• Name: Tumor protein p53 (TP53) ,Homo sapiens
• Synonyms: Stress-induced protein; p53-dependent damage-inducible nuclear protein 1
• Molecule Type: Protein
• Gene Name: TP53INP1
• Gene ID: 94241
• Location: chr8:94925972-94949378[-]
• Sequence:
  MFQRLNKMFVGEVSSSSNQEPEFNEKEDDEWILVDFIDTCTGFSAEEEEEEEDISEESPT
  EHPSVFSCLPASLECLADTSDSCFLQFESCPMEESWFITPPPCFTAGGLTTIKVETSPME
  NLLIEHPSMSVYAVHNSCPGLSEATRGTDELHSPSSPRVEAQNEMGQHIHCYVAALAAHT
  TFLEQPKSFRPSQWIKEHSERQPLNRNSLRRQNLTRDCHPRQVKHNGWVVHQPCPRQYNY
• Function: Antiproliferative and proapoptotic protein involved in cell stress response which acts as a dual regulator of transcription and autophagy. Acts as a positive regulator of autophagy. In response to cellular stress or activation of autophagy, relocates to autophagosomes where it interacts with autophagosome-associated proteins GABARAP, GABARAPL1/L2, MAP1LC3A/B/C and regulates autophagy. Acts as an antioxidant and plays a major role in p53/TP53-driven oxidative stress response. Possesses both a p53/TP53-independent intracellular reactive oxygen species (ROS) regulatory function and a p53/TP53-dependent transcription regulatory function. Positively regulates p53/TP53 and p73/TP73 and stimulates their capacity to induce apoptosis and regulate cell cycle. In response to double-strand DNA breaks, promotes p53/TP53 phosphorylation on 'Ser-46' and subsequent apoptosis. Acts as a tumor suppressor by inducing cell death by an autophagy and caspase-dependent mechanism. Can reduce cell migration by regulating the expression of SPARC. .
• Uniprot ID: T53I1_HUMAN
• Ensembl ID: ENSG00000164938
• HGNC ID: HGNC:18022

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

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: PDXs model; Mice
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Therefore, in the present study, we set out to reprocess and reanalyze the PDAC PDX gene expression data produced by Yang et al. (referred to as the Yang dataset hereafter) using our validated pipeline to identify markers of intrinsic and acquired resistance to gemcitabine. The association between presence of pathogenic TP53 mutations and gemcitabine response was also examined.

Ibrutinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Diffuse large B-cell lymphoma [ICD-11: 2A81.0] [2]

• Metabolic Type: Redox metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CD40L cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: OCI-LY10 cells; Blood; Homo sapiens (Human); CVCL_8795
• In Vitro Model: OCI-LY18 cells; Blood; Homo sapiens (Human); CVCL_1880
• In Vitro Model: OCI-LY19 cells; Bone marrow; Homo sapiens (Human); CVCL_1878
• In Vitro Model: OCI-LY3 cells; Blood; Homo sapiens (Human); CVCL_8800
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: U-2932 cells; Blood; Homo sapiens (Human); CVCL_1896
• In Vitro Model: Val cells; Bone marrow; Homo sapiens (Human); CVCL_1819
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Treatment with AZD5991 restricted growth of DLBCL cells independent of cell of origin and overcame ibrutinib resistance in MCL cells. Mcl-1 inhibition led to mitochondrial dysfunction as manifested by mitochondrial membrane depolarization, decreased mitochondrial mass, and induction of mitophagy. This was accompanied by impairment of oxidative phosphorylation. TP53 and BAX were essential for sensitivity to Mcl-1, and oxidative phosphorylation was implicated in resistance to Mcl-1 inhibition.

Inotuzumab ozogamicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Mature B-cell neoplasms [.] [3]

• Resistant Disease: Mature B-cell neoplasms [.]
• Resistant Drug: Inotuzumab ozogamicin
• Molecule Alteration: Missense mutation; Methylation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: pre-InO and/or post-InO tumor cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: GeneSeq assay; Mutation assay
• Mechanism Description: Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape.

Lovastatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [4]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Lovastatin
• Molecule Alteration: Expression; Rv3795; p.Glu378Ala
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI- H460 cells; Pleural effusion; Homo sapiens (Human); CVCL_0459
• In Vitro Model: NCI-H1299 cells; Lymph node; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H1355 cells; Pleural effusion; Homo sapiens (Human); CVCL_1464
• In Vitro Model: CL1-0 cells; Lung; Homo sapiens (Human); CVCL_3871
• In Vitro Model: CL1-6 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: MTT assay; Cell viability assay
• Mechanism Description: Therefore, the drug sensitivity of DOC and lovastatin in human lung cancer cells was evaluated. We found that H1355 (mutant TP53-E285K), CL1 (mutant TP53-R248W), and H1299 (TP53-null) human non-small cell lung cancer cells were more sensitive to lovastatin than A549 and H460 cells expressing wild-type TP53. Conversely, A549 and H460 cells showed higher sensitivity to DOC than H1299 and CL1 cells, as demonstrated by the MTT assay. When endogenous TP53 activity was inhibited by pifithrin-alpha in A549 and H460 cells, lovastatin sensitivities significantly increased, and cancer cell viabilities markedly reduced. These results indicate that TP53 status is associated with the anti-cancer effect of statins in human lung cancer cells. Mutated or null TP53 status is correlated with higher statin sensitivity. Furthermore, DOC-resistant H1299 (H1299/D8) cells showed significant sensitivity to lovastatin treatment compared to DOC-resistant A549 (A549/D16) cells, indicating a potential application of statins/chemotherapy combination therapy to control wild-type and abnormal TP53-containing human lung tumors.

References

• Ref 1: Insights into gemcitabine resistance in pancreatic cancer: association with metabolic reprogramming and TP53 pathogenicity in patient derived xenografts. J Transl Med. 2024 Aug 5;22(1):733.
• Ref 2: Pharmacologic Targeting of Mcl-1 Induces Mitochondrial Dysfunction and Apoptosis in B-Cell Lymphoma Cells in a TP53- and BAX-Dependent Manner. Clin Cancer Res. 2021 Sep 1;27(17):4910-4922.
• Ref 3: Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL. Blood. 2024 Jul 4;144(1):61-73.
• Ref 4: Association of Wild-Type TP53 with Downregulation of Lovastatin Sensitivity in Human Non-Small Cell Lung Cancer Cells. Curr Issues Mol Biol. 2024 Sep 13;46(9):10130-10139.