Lack of functional retinoblastoma protein mediates increased resistance to antimetabolites in human sarcoma cell lines Journal Article

   


Authors: Li, W.; Fan, J.; Hochhauser, D.; Banerjee, D.; Zielinski, Z.; Almasan, A.; Yin, Y.; Kelly, R.; Wahl, G. M.; Bertino, J. R.
Article Title: Lack of functional retinoblastoma protein mediates increased resistance to antimetabolites in human sarcoma cell lines
Abstract: Growth inhibition assays indicated that the IC50 values for methotrexate (MTX) and 5-fluorodeoxyuridine (FdUrd) in HS-18, a liposarcoma cell line lacking retinoblastoma protein (pRB), and SaOS-2, an osteosarcoma cell line with a truncated and nonfunctional pRB, were 10- to 12-fold and 4- to II- fold higher, respectively, than for the HT-1080 (fibrosarcoma) cell line, which has wild-type pRB. These Rb(-/-) cell lines exhibited a 2- to 4-fold increase in both dihydrofolate reductase (DHFR) and thymidylate synthase (TS) enzyme activities as well as a 3- to 4-fold increase in mRNA levels for these enzymes compared to the HT-1080 (Rb(+/+)) cells. This increase in expression was not due to amplification of the DHFR and TS genes. Growth inhibition by MTX and FdUrd was increased and DHFR and TS activities and expression were correspondingly decreased in Rb transfectants of SaOS-2 cells. In contrast, there was no significant difference in growth inhibition among these cell lines for the nonantimetabolites VP-16, cisplatin, and doxorubicin. A gel mobility-shift assay showed that parental SaOS-2 cells had increased levels of free E2F compared to the Rb-reconstituted NaOS-2 cells. These results indicate that pRB defective cells may have decreased sensitivity to growth inhibition by target enzymes encoded by genes whose transcription is enhanced by E2F proteins and suggest mechanisms of interaction between cytotoxic agents and genes involved in cell cycle progression.
Keywords: osteosarcoma; bone neoplasms; human cell; cisplatin; doxorubicin; antineoplastic agents; comparative study; methotrexate; cell cycle; cell division; antimetabolites, antineoplastic; etoposide; cell line; genetic transcription; drug resistance, neoplasm; tumor cells, cultured; transfection; sarcoma; cancer inhibition; tumor suppressor gene; molecular sequence data; fibrosarcoma; recombinant proteins; base sequence; thymidylate synthase; tetrahydrofolate dehydrogenase; floxuridine; retinoblastoma protein; liposarcoma; growth inhibition; oligonucleotide probes; human; priority journal; article; support, non-u.s. gov't; support, u.s. gov't, p.h.s.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 92
Issue: 22
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 1995-10-24
Start Page: 10436
End Page: 10440
Language: English
DOI: 10.1073/pnas.92.22.10436
PUBMED: 7479800
PROVIDER: scopus
PMCID: PMC40812
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-0028871672&doi=10.1073%2fpnas.92.22.10436&partnerID=40&md5=25435b00ef01b91fdc14173c2933a355
Notes: Article -- Export Date: 28 August 2018 -- Source: Scopus
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MSK Authors
  1. Weiwei Li
    63 Li
  2. Debabrata Banerjee
    136 Banerjee
  3. Jianguo Fan
    30 Fan
  4. Joseph Bertino
    363 Bertino
  5. Daniel Hochhauser
    15 Hochhauser
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