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Enhanced sensitivity to tumor necrosis factor‐α in doxorubicin‐resistant tumor cell lines due to down‐regulated c‐erbB2
Author(s) -
Sleijfer Stefan,
Asschert Johanna G. W.,
TimmerBosscha Hetty,
Mulder Nanno H.
Publication year - 1998
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19980703)77:1<101::aid-ijc16>3.0.co;2-h
Subject(s) - doxorubicin , tumor necrosis factor alpha , cancer research , tumor cells , cell culture , medicine , biology , chemotherapy , genetics
We have studied the relationship between tumor necrosis factor (TNF)‐sensitivity and doxorubicin‐resistance in our doxorubicin‐resistant cell line panel consisting of the parental cell line GLC 4 plus GLC 4 ‐Adr 2x and GLC 4 ‐Adr 350x with respective resistance factors of 2 and 350 compared with GLC 4 . At the highest dose of 1000 ng/ml TNF, GLC 4 was almost completely resistant to TNF, whereas 37% and 68% growth inhibition was observed in GLC 4 ‐Adr 2x and GLC 4 ‐Adr 350x , respectively. Sensitivity to TNF appeared to correlate inversely with the expression and gene copies of topoisomerase IIα in these cell lines. The gene encoding for c‐erbB2 is in the proximity of the topoisomerase IIα gene and its product is a known cause for TNF‐resistance. We found that our doxorubicin‐resistant cell lines with decreased topoisomerase IIα gene copies have a simultaneous decrease in c‐erbB2 gene copies, probably due to linkage between these 2 genes. This reduced number of c‐erbB2 gene copies resulted in decreased c‐erbB2 expression and subsequently in increased sensitivity to TNF. Additionally, we tried to establish some of the mechanisms associated with TNF‐resistance in GLC 4 related to c‐erbB2 overexpression. There was no difference in TNF‐receptor‐1 expression between the cell lines. Compared with the TNF‐sensitive GLC 4 ‐Adr 350x , GLC 4 appeared to have a decreased activation of NF‐κB after exposure to TNF that might indicate a reduced TNF‐receptor function. In GLC 4 , increased Bcl‐2 expression was found, a protein described to confer TNF‐resistance. Moreover, it was demonstrated that combining TNF with the poly‐ADP‐ribose polymerase (PARP) inhibitors 6‐aminonicotinamide and 3‐aminobenzamide did not affect TNF‐sensitivity in GLC 4 and GLC 4 ‐Adr 350x , excluding a pivotal role of PARP in TNF‐resistance in these cell lines. In conclusion, our data show that doxorubicin‐resistant tumor cell lines with decreased topoisomerase IIα gene copies can become sensitive to TNF due to loss of c‐erbB2 gene copies. We also found that several mechanisms associated with c‐erbB2 overexpressing contribute to TNF‐resistance in GLC 4 . Int. J. Cancer 77:101–106, 1998.© 1998 Wiley‐Liss, Inc.