TabBO: a model reflecting common molecular features of androgen-independent prostate cancer.
We established two human prostate cancer cell lines, MDA PCa 2a and MDA PCa 2b, the TabBO model system, that reflect common features of human androgen-independent prostate cancer that are not present in other model systems: bone origin, prostate-specific antigen production, androgen receptor expression, and androgen sensitivity. We therefore hypothesized that molecular pathways in our model system reflect common alterations responsible for the progression of a subset of human prostate cancer. Progression to androgen independence has been hypothesized to be largely associated with impairment of the regulation of cell growth or apoptosis of prostate cancer cells. Therefore, in this study, we examined molecular markers known or suspected to be important in prostate cancer progression and key regulators of cell growth and apoptosis: p53, p21WAF1/CIP1, Bcl-2, Bax, retinoblastoma (Rb), and p16INK4A/MITS1. We analyzed the expression of these markers in the cell lines, their tumor of origin, and tumors derived from the cell lines by s.c. inoculation into nude mice. DNA sequencing of the entire open reading frames of the p53 and p21 genes revealed no mutations. Additionally, accumulation of the p53 protein was not found by Western blot analysis, nor was overexpression of the Bcl-2 oncoprotein detected. Bax expression was detected in MDA PCa 2a cells, whereas it was absent in MDA PCa 2b. Rb and p16 protein expression was normal as measured by both Western blot and immunochemical analyses. Immunohistochemical studies of p53, p21, Bcl-2, and Rb in both samples from the original human cancer from which the lines were derived and mouse xenografts derived from the lines revealed similar levels of protein. These results are consistent with reports indicating that 40-50% of bone metastases of prostate cancer have wild-type p53, 50-70% do not overexpress the Bcl-2 protein, and mutations in the p21 gene are rare. Therefore, we conclude that MDA PCa 2a and MDA PCa 2b reflect molecular pathways in a common subset of human androgen-independent prostate cancer and that important molecular players in apoptosis (namely, p53 and Bcl-2) seem to be intact in this subset of androgen-independent prostate cancer. Understanding the signal-transduction pathways operating in these cell lines may help to identify therapeutic targets for prostate cancer.
Navone
N M
NM
Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Rodriquez-Vargas
M C
MC
Benedict
W F
WF
Troncoso
P
P
McDonnell
T J
TJ
Zhou
J H
JH
Luthra
R
R
Logothetis
C J
CJ
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis / Q000235:genetics; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009154:Mutation; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D016160:Retinoblastoma Protein / Q000032:analysis; D017422:Sequence Analysis, DNA; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics; D051028:bcl-2-Associated X Protein
D000728:Androgens; C494826:BAX protein, human; C494827:Bax protein, mouse; C493956:CDKN1A protein, human; D002352:Carrier Proteins; C493957:Cdkn1a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein