RGD Reference Report - Combination of proteasome and HDAC inhibitors for uterine cervical cancer treatment. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

Combination of proteasome and HDAC inhibitors for uterine cervical cancer treatment.

Authors: Lin, Z  Bazzaro, M  Wang, MC  Chan, KC  Peng, S  Roden, RB 
Citation: Lin Z, etal., Clin Cancer Res. 2009 Jan 15;15(2):570-7.
RGD ID: 2306200
Pubmed: PMID:19147762   (View Abstract at PubMed)
PMCID: PMC2714480   (View Article at PubMed Central)
DOI: DOI:10.1158/1078-0432.CCR-08-1813   (Journal Full-text)

PURPOSE: Cervical cancer cells are addicted to the expression of the human papillomavirus (HPV) oncoproteins E6 and E7. The oncogencity of E6 is mediated in part by targeting p53 and PDZ-family tumor suppressor proteins for rapid proteasomal degradation, whereas the E7 oncoprotein acts in part by coopting histone deacetylases (HDAC)1/2. Here, we examine the hypothesis that inhibition of proteasome function and HDAC activity would synergistically and specifically trigger cervical cancer cell death by the interruption of E6 and E7 signaling. EXPERIMENTAL DESIGN: The sensitivity and molecular responses of keratinocytes and HPV-positive and HPV-negative cervical cancer cells and xenografts to combinations of proteasome and HDAC inhibitors were tested. The expression of HDAC1/HDAC2 in situ was examined in cervical cancer, its precursors, and normal epithelium. RESULTS: Cervical cancer cell lines exhibit greater sensitivity to proteasome inhibitors than do HPV-negative cervical cancers or primary human keratinocytes. Treatment of cervical cancer cells with bortezomib elevated the level of p53 but not hDlg, hScribble or hMAGI. Immunohistochemical analysis revealed elevated HDAC1/HDAC2 expression in cervical dysplasia and cervical carcinoma versus normal cervical epithelium. The combination of bortezomib and HDAC inhibitor trichostatin A or vorinostat shows synergistic killing of HPV-positive, but not HPV-negative, cervical cancer cell lines. Similarly, treatment of HeLa xenografts with the combination of bortezomib and trichostatin A retarded tumor growth significantly more effectively than either agent alone. CONCLUSIONS: A combination of proteasome and HDAC inhibitors, including bortezomib and vorinostat, respectively, warrants exploration for the treatment of cervical cancer.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cervix uteri carcinoma in situ  IEP 2306200; 2306200; 2306200protein:increased expression:uterine cervixRGD 
cervix uteri carcinoma in situ  ISOHDAC1 (Homo sapiens)2306200; 2306200protein:increased expression:uterine cervixRGD 
cervix uteri carcinoma in situ  ISOHDAC2 (Homo sapiens)2306200; 2306200protein:increased expression:uterine cervixRGD 
cervix uteri carcinoma in situ  ISOHDAC6 (Homo sapiens)2306200; 2306200protein:increased expression:uterine cervixRGD 
Uterine Cervical Neoplasms  IEP 2306200; 2306200; 2306200protein:increased expression:uterine cervixRGD 
Uterine Cervical Neoplasms  ISOHDAC1 (Homo sapiens)2306200; 2306200protein:increased expression:uterine cervixRGD 
Uterine Cervical Neoplasms  ISOHDAC2 (Homo sapiens)2306200; 2306200protein:increased expression:uterine cervixRGD 
Uterine Cervical Neoplasms  ISOHDAC6 (Homo sapiens)2306200; 2306200protein:increased expression:uterine cervixRGD 

Objects Annotated

Genes (Rattus norvegicus)
Hdac1  (histone deacetylase 1)
Hdac2  (histone deacetylase 2)
Hdac6  (histone deacetylase 6)

Genes (Mus musculus)
Hdac1  (histone deacetylase 1)
Hdac2  (histone deacetylase 2)
Hdac6  (histone deacetylase 6)

Genes (Homo sapiens)
HDAC1  (histone deacetylase 1)
HDAC2  (histone deacetylase 2)
HDAC6  (histone deacetylase 6)


Additional Information