Camptothecin induces p53-dependent and -independent apoptogenic signaling in melanoma cells

Abstract

Various DNA-targeting agents may initiate p53-dependent as well as p53-independent response and subsequent apoptosis via alternative cellular systems which include for instance p73, caspase-2 or Bcl-2 family proteins. The scope of involvement of individual molecules in this process and the mechanisms governing their potential interplay are still not entirely understood, in particular in highly aggressive cancers such as in malignant melanoma. In this work we investigated the role and involvement of both p53-dependent and -independent mechanisms in selected melanoma cell lines with differing status of p53 using a model DNA topoisomerase I inhibitor camptothecin (CPT). Here we report that CPT induced in Bowes melanoma cells apoptosis which is essentially p53 and mitochondria-dependent but with some involvement of caspase-2 and p73. Conversely, in mutant p53 melanoma cells overall levels of CPT-induced apoptosis are significantly lower, with p73 and caspase-2 signaling playing important roles. In addition, in these cells the expression of micro RNAs family 34 (miR-34) were low compared to wild-type p53 cells. The ectopic expression of wild type p53 than restored apoptotic response of cells to CPT despite the fact that the expression of miR-34 and miR-155 were not influenced. These results suggest that CPT induces multivariate cellular stress responses including activation of DNA-damage response-p53 pathway as well as p53-independent signaling and their mutual crosstalk play the decisive role in the efficient triggering of apoptosis in melanoma cells.

c-MYC-Induced Sebaceous Gland Differentiation Is Controlled by an Androgen Receptor/p53 Axis

“…Consistent with the stimulation of differentiation, there was reduced expression of Ki67 (Figure 6H) and of Keratin 7 (K7), a sebaceous lineage marker (Zouboulis et al., 1999) that is expressed in the SG basal layer (Ju et al., 2011) (Figure 6I). Conversely, when p53 activation in 4OHT-treated K14MycER mice was enhanced by daily application of camptothecin (a topoisomerase inhibitor that causes DNA breaks and activates p53 [Rudolf et al., 2011]) (Figures S5C–S5F), AR activity and proliferation in the SG lineage were reduced resulting in a reduction in gland size (Figure S5F). Testosterone coapplication partially antagonized the effects of camptothecin on the SG (Figures S5C–S5F).…”

The PARP inhibitor ABT-888 synergizes irinotecan treatment of colon cancer cell lines

“…Here we show that treatment with ABT-888, at concentrations well below clinically achievable levels [10,12,13], sensitized both p53 wild type and mutant colon cancer cells lines to SN38 induced death in vitro. SN38, the active metabolite of irinotecan, is a potent topoisomerase I (topo 1) inhibitor that through its' interaction inhibits the separation of topo I from the DNA strand and can result in the formation of DSBs [40,41]. In healthy cells, this damage can be rapidly repaired via the major DNA damage repair pathways, HR and NHEJ.…”

Restoring the tumour suppressive function of p53 as a parallel strategy in melanoma therapy

“…In contrast, TAp73 plays a role of tumour suppressive role in melanoma. In wild type p53-expressing melanoma cells, camptothecin, a cytotoxic quinoline alkaloid which inhibits the DNA enzyme topoisomerase I, induces p53-and p73-dependent apoptosis whereas in mutant p53-expressing melanoma cells, p73 and caspase-2 are predominantly involved in inducing apoptosis [63]. Recently, a study confirmed the involvement of TAp73 in inducing apoptosis in melanoma [64].…”