On the role of different signal transduction pathways in induction of apoptosis by anticancer drugs

Anticancer drug treatment gives rise to complex cellular responses in tumor cells. An improved understanding of the mechanisms underlying these responses is important in order to improve treatment. It is also of importance to investigate novel mechanisms of drug action that could potentially represent new concepts for treatment. In this thesis, both clinically used anticancer agents as well as other agents inducing tumor cell death were studied.

The DNA damaging agents cisplatin and ellipticine were shown to also exert non-nuclear effects important for apoptotic signaling such as induction of endoplasmic reticulum stress and for cisplatin also generation of reactive oxygen species. Cisplatin was shown to trigger distinct cellular outcomes depending on the concentration used. Our data suggest that DNA damage signaling primarily induces senescence. Acute apoptosis is mostly independent of DNA damage responses and is rather triggered by cytoplasmic events such as generation of reactive oxygen species.

A chemical library was screened for compounds inducing apoptosis independently of p53. It was found that lysosomes often are involved in p53-independent apoptotic signaling. Lysosomal apoptosis signaling was further examined by screening for compounds that induce cathepsin-dependent apoptosis. Among the most potent agents identified were two compounds with similar chemical structures that were found to induce the accumulation of polyubiquitins in cells. Our data raise the possibility that inhibition of the ubiquitin-proteasomal system may lead to the triggering of lysosomal membrane permeabilization.

Apoptosis induction by the anticancer agent paclitaxel was examined with a focus on the potential involvement of the proapoptotic protein Bad. We found Bad to be phosphorylated at Ser 128, a site reported to enhance its proapoptotic activity, after paclitaxel treatment. Our data does not however suggest an important role for this phosphorylation event in paclitaxel-induced apoptosis.

The studies in this thesis illustrate the complexity of cellular responses triggered by anticancer drugs. The signaling pathways often involve different cellular organelles and the outcome of treatment can include various forms of antiproliferative responses.

List of scientific papers

I. Berndtsson M, Konishi Y, Bonni A, Hagg M, Shoshan M, Linder S, Havelka AM (2005). "Phosphorylation of BAD at Ser-128 during mitosis and paclitaxel-induced apoptosis." FEBS Lett 579(14): 3090-4
https://pubmed.ncbi.nlm.nih.gov/15907327

II. Hagg M, Berndtsson M, Mandic A, Zhou R, Shoshan MC, Linder S (2004). "Induction of endoplasmic reticulum stress by ellipticine plant alkaloids." Mol Cancer Ther 3(4): 489-97
https://pubmed.ncbi.nlm.nih.gov/15078993

III. Berndtsson M, Hagg M, Panaretakis T, Havelka AM, Shoshan MC, Linder S (2007). "Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA." Int J Cancer 120(1): 175-80
https://pubmed.ncbi.nlm.nih.gov/17044026

IV. Erdal H, Berndtsson M, Castro J, Brunk U, Shoshan MC, Linder S (2005). "Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis." Proc Natl Acad Sci U S A 102(1): 192-7. Epub 2004 Dec 23
https://pubmed.ncbi.nlm.nih.gov/15618392

V. Berndtsson M, Beaujouin M, Mandic Havelka A, Larsson R, Westman J, Liaudet-Coopman E, Linder S (2007). "Induction of cathepsin-dependent apoptosis by inhibitors of the ubiquitin-proteasome system." (Manuscript)