TY  - JOUR
A1  - Ehrenschwender, M.
A1  - Bittner, S.
A1  - Seibold, K.
A1  - Wajant, H.
T1  - XIAP-targeting drugs re-sensitize PIK3CA-mutated colorectal cancer cells for death receptor-induced apoptosis
JF  - Cell Death & Disease
N2  - Mutations in the oncogenic PIK3CA gene are found in 10-20% of colorectal cancers (CRCs) and are associated with poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic TRAIL death receptor antibodies emerged as promising anti-neoplastic therapeutics, but to date failed to prove their capability in the clinical setting as especially primary tumors exhibit high rates of TRAIL resistance. In our study, we investigated the molecular mechanisms underlying TRAIL resistance in CRC cells with a mutant PIK3CA (PIK3CA-mut) gene. We show that inhibition of the constitutively active phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway only partially overcame TRAIL resistance in PIK3CA-mut-protected HCT116 cells, although synergistic effects of TRAIL plus PI3K, Akt or cyclin-dependent kinase (CDK) inhibitors could be noted. In sharp contrast, TRAIL triggered full-blown cell death induction in HCT116 PIK3CA-mut cells treated with proteasome inhibitors such as bortezomib and MG132. At the molecular level, resistance of HCT116 PIK3CA-mut cells against TRAIL was reflected by impaired caspase-3 activation and we provide evidence for a crucial involvement of the E3-ligase X-linked inhibitor of apoptosis protein (XIAP) therein. Drugs interfering with the activity and/or the expression of XIAP, such as the second mitochondria-derived activator of caspase mimetic BV6 and mithramycin-A, completely restored TRAIL sensitivity in PIK3CA-mut-protected HCT116 cells independent of a functional mitochondrial cell death pathway. Importantly, proteasome inhibitors and XIAP-targeting agents also sensitized other CRC cell lines with mutated PIK3CA for TRAIL-induced cell death. Together, our data suggest that proteasome-or XIAP-targeting drugs offer a novel therapeutic approach to overcome TRAIL resistance in PIK3CA-mutated CRC.
KW  - trail-mediated apoptosis
KW  - ligand trail
KW  - CASPASE-3
KW  - resistance
KW  - BH3-only proteins
KW  - inhibitor
KW  - MCL-1
KW  - degradation
KW  - activation
KW  - carcinoma
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114374
SN  - 2041-4889
VL  - 5
ER  - 
TY  - JOUR
A1  - Seibold, Sebastian
A1  - Hothorn, Torsten
A1  - Gossner, Martin M.
A1  - Simons, Nadja K.
A1  - Blüthgen, Nico
A1  - Müller, Jörg
A1  - Ambarlı, Didem
A1  - Ammer, Christian
A1  - Bauhus, Jürgen
A1  - Fischer, Markus
A1  - Habel, Jan C.
A1  - Penone, Caterina
A1  - Schall, Peter
A1  - Schulze, Ernst‐Detlef
A1  - Weisser, Wolfgang W.
T1  - Insights from regional and short‐term biodiversity monitoring datasets are valuable: a reply to Daskalova et al. 2021
JF  - Insect Conservation and Diversity
N2  - Reports of major losses in insect biodiversity have stimulated an increasing interest in temporal population changes. Existing datasets are often limited to a small number of study sites, few points in time, a narrow range of land‐use intensities and only some taxonomic groups, or they lack standardised sampling. While new monitoring programs have been initiated, they still cover rather short time periods.
Daskalova et al. 2021 (Insect Conservation and Diversity, 14, 1‐18) argue that temporal trends of insect populations derived from short time series are biased towards extreme trends, while their own analysis of an assembly of shorter‐ and longer‐term time series does not support an overall insect decline. With respect to the results of Seibold et al. 2019 (Nature, 574, 671–674) based on a 10‐year multi‐site time series, they claim that the analysis suffers from not accounting for temporal pseudoreplication.
Here, we explain why the criticism of missing statistical rigour in the analysis of Seibold et al. (2019) is not warranted. Models that include ‘year’ as random effect, as suggested by Daskalova et al. (2021), fail to detect non‐linear trends and assume that consecutive years are independent samples which is questionable for insect time‐series data.
We agree with Daskalova et al. (2021) that the assembly and analysis of larger datasets is urgently needed, but it will take time until such datasets are available. Thus, short‐term datasets are highly valuable, should be extended and analysed continually to provide a more detailed understanding of insect population changes under the influence of global change, and to trigger immediate conservation actions.
KW  - Arthropod
KW  - biodiversity
KW  - insect decline
KW  - land use
KW  - time series
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228309
VL  - 14
IS  - 1
SP  - 144
EP  - 148
ER  -