Der konträre Einfluss von p53 auf die extrinsische und intrinsische Apoptoseinduktion in Tumorzellen

In the past view decades the therapy of malignant diseases has
improved significantly. However especially metastatic diseases and
relapses still require the development of new therapeutic
modalities. Most chemotherapeutic agents induce apoptosis. A better
understanding of apoptosis signaling is needed in order to combine
cytostatic drugs in a more efficient way and to develop new
targeted therapies. Conventional cytotoxic drugs and new therapies
target p53, a key regulator of apoptosis. p53 is one of the most
intensively studied target proteins but the heterogeneity and
diversity of the function of p53 remains unclear. We investigated
the importance of p53 in the intrinsic and extrinsic apoptosis
signaling, via a variety of molecular biological approaches
(Wachter et al., 2013). Apoptosis is induced intrinsically by the
release of pro-apoptotic proteins from the inter-membrane space of
the mitochondrion (eg. doxorubicin) or via activation of death
receptors on the surface of the cell (eg. TRAIL, Tumor necrosis
factor Related Apoptosis Inducing Ligand). As described in the
literature, wildtype p53 leaded to an increase in intrinsic cell
death, whereas different p53 mutations reduced apoptosis. In our
work we discovered that the influence of p53 status on extrinsic
cell death induction was much more multifaceted. The presence of
p53 in tumor cell lines and xenograft tumor cells resulted in
augmented, unaffected or decreased cell death. With great interest
we discovered that the replacement of wildtype p53 by mutant p53
did not disturb the extrinsic apoptosis inducing capacity. As a
next step we studied the influence of cell cycle arrest induced by
p53 activation on TRAIL apoptosis sensitivity (Ehrhardt/Wachter et
al., 2013). Cell cycle arrest was induced in tumor cell lines and
patient samples in G0, G1 or G2 with cytostatic drugs,
phase-specific inhibitors or RNA interference against cyclinB and
E. Molecular or biochemical arrest at any point of the cell cycle
augmented the rate of apoptosis by TRAIL. Consequently, when cell
cycle arrest was deactivated by adding caffeine, the antitumor
activity of TRAIL was decreased. The extrinsic apoptosis by TRAIL
was increased in senescent tumor cells. This is especially
important for the therapy of minimal residual disease and for the
prevention of relapse caused by resting tumor cells. Additionally,
we studied the impact of p53 activation on the rate of apoptosis
induced by combinations of cytostatic drugs (Ehrhardt, Schrembs,
Moritz, Wachter et al., 2011). A single drug is not very effective
in cancer therapy therefore malignant diseases are usually treated
with a combination of cytostatic agents. Co-administration of
anthracyclines and vinca alkaloids on the same day is a standard of
care for hematopoietic malignancies. If both drugs are applied
simultaneously, doxorubicin inhibits apoptosis induction of
vincristine. While it is well understood that doxorubicin activates
p53 and induces cell-cycle arrest, we observed that cell-cycle
arrest disabled inactivation of anti-apoptotic Bcl-2-family members
by vincristine. Therefore, it follows that vincristine was unable
to activate downstream apoptosis signaling. Cycling cells are
required for vincristine to kill cancer cells efficiently. In
summary we have shown the heterogeneity of p53 in extrinsic and
intrinsic apoptosis signaling. The impact of the p53 status of
tumor cells on extrinsic apoptosis signaling should be considered,
especially in the context of therapeutic approaches that aim to
restore p53 function to enable cell death. p53 can act pro- and
anti-apoptotic, depending on the individual patient tumor cell and
on drug and signal interactions. Finally, this suggests that
patients benefit from an individualized therapeutic regimen.
Further investigation is required in order to better understand the
therapeutic potential of these complex interactions.