Signaling and drug sensitivity.
Even though alterations in receptor and nonreceptor kinases are involved in the development of human cancer, many cancer cell lines still retain their responsiveness to growth factors. We have investigated the hypothesis that cellular signaling events regulate the sensitivity of cancer cells to chemotherapeutic agents. In 2008 human ovarian carcinoma cells, activation of a number of different transduction pathways resulted in a 2 to 4-fold increase in the sensitivity to cisplatin. These signaling events include pathways activated by the epidermal growth factor (EGF) receptor, tumor necrosis factor alpha (TNF alpha) receptor, bombesin receptor, protein kinase A (PKA), and protein kinase C (PKC). Enhanced sensitivity to chemotherapeutic agents is presumed to be mediated by phosphorylation of critical target protein(s). beta-tubulin has been identified as one such target for the protein kinase signaling cascade. For other signal transduction pathways the key substrates that regulate drug sensitivity have not yet been identified. Recent work has shown that DNA damaging agents activate signaling cascades one of which involves the Src, Ras, and Raf proteins as intermediates and results in induction of a number of genes, including c-fos, c-jun, and the growth arrest and DNA damage-inducible (gadd) genes. This signaling cascade has been shown to involve activation of protein kinase C and to have a protective function. With the growing understanding of how signaling events relate to damage response and drug sensitivity, new and potentially useful strategies for modulating drug sensitivity are evolving.
Christen
R D
RD
Department of Medicine, University of California San Diego, La Jolla, CA 92093-0812.
Isonishi
S
S
Jones
J A
JA
Jekunen
A P
AP
Hom
D K
DK
Kröning
R
R
Gately
D P
DP
Thiebaut
F B
FB
Los
G
G
Howell
S B
SB
D000818:Animals; D002945:Cisplatin / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D002945:Cisplatin