Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer

Scherr, Anna-Lena; Möck, Andreas; Gdynia, Georg; Schmitt, Nathalie; Heilig, Christoph E.; Korell, Felix; Rhadakrishnan, Praveen; Hoffmeister, Paula; Metzeler, Klaus H.; Schulze‐Osthoff, Klaus; Illert, Anna Lena; Boerries, Melanie; Trojan, Jörg; Waidmann, Oliver; Falkenhorst, Johanna; Siveke, Jens T.; Jost, Philipp J.; Bitzer, Michael; Malek, Nisar P.; Vecchione, Loredana; Jelas, Ivan; Brors, Benedikt; Glimm, Hanno; Grekova, Svetlana; Gehrig, Tobias; Schulze‐Bergkamen, Henning; Jäger, Dirk; Schirmacher, Peter; Heikenwälder, Mathias; Goeppert, Benjamin; Schneider, Martin; Fröhling, Stefan; Köhler, Bruno

doi:10.1038/s41419-020-03092-7

Cited by 27 publications

(22 citation statements)

References 56 publications

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“…BCL2L1 upregulation was found in different tumors [72][73][74][75][76][77]. In the study of a large cohort of colorectal cancers, BCL-XL, but not BCL2 or MCL-1, emerged as a highly active protein, and its transcript level was the highest among the anti-apoptotic BCL2 genes [77].…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that BCL-XL is about 10 times more efficient than BCL2 in preventing doxorubicininduced apoptosis [101]. Inhibition of BCL-XL induced apoptosis and enhanced the effectiveness of chemotherapeutic agents in colorectal cancer cell lines [77]. Recently, a number of therapeutics targeting the BCL2 family has already been introduced into treatment or is now under investigation.…”

Section: Discussionmentioning

confidence: 99%

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Transcript-Level Dysregulation of BCL2 Family Genes in Acute Myeloblastic Leukemia

Handschuh

Wojciechowski

Kaźmierczak

et al. 2021

Cancers

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The expression of apoptosis-related BCL2 family genes, fine-tuned in normal cells, is dysregulated in many neoplasms. In acute myeloid leukemia (AML), this problem has not been studied comprehensively. To address this issue, RNA-seq data were used to analyze the expression of 26 BCL2 family members in 27 AML FAB M1 and M2 patients, divided into subgroups differently responding to chemotherapy. A correlation analysis, analysis of variance, and Kaplan-Meier analysis were applied to associate the expression of particular genes with other gene expression, clinical features, and the presence of mutations detected by exome sequencing. The expression of BCL2 family genes was dysregulated in AML, as compared to healthy controls. An upregulation of anti-apoptotic and downregulation of pro-apoptotic genes was observed, though only a decrease in BMF, BNIP1, and HRK was statistically significant. In a group of patients resistant to chemotherapy, overexpression of BCL2L1 was manifested. In agreement with the literature data, our results reveal that BCL2L1 is one of the key players in apoptosis regulation in different types of tumors. An exome sequencing data analysis indicates that BCL2 family genes are not mutated in AML, but their expression is correlated with the mutational status of other genes, including those recurrently mutated in AML and splicing-related. High levels of some BCL2 family members, in particular BIK and BCL2L13, were associated with poor outcome.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transcript-Level Dysregulation of BCL2 Family Genes in Acute Myeloblastic Leukemia

Handschuh

Wojciechowski

Kaźmierczak

et al. 2021

Cancers

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“…The combined Bcl-2/Bcl-x L inhibitor ABT-263 showed in clinical trials dose-limiting side effects with thrombocytopenia, attributed to inhibition of Bcl-x L , and leukocytopenia, due to Bcl-2 inhibition [ 39 , 40 , 41 ]. After treatment with WEHI-539 in mouse models, low levels of erythrocytes and hemoglobin were observed [ 42 ]. We were able to use lower doses by combining Bcl-x L inhibition with radiotherapy, thereby reducing the probability of adverse effects while still managing to obtain a notable increase in cell death.…”

Section: Discussionmentioning

confidence: 99%

Specific Targeting of Antiapoptotic Bcl-2 Proteins as a Radiosensitizing Approach in Solid Tumors

Sobol

Nieto

Eberlein

et al. 2022

IJMS

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Avoidance of therapy-induced apoptosis is a hallmark of acquired resistance towards radiotherapy. Thus, breaking resistance still challenges modern cancer therapy. The Bcl-2 protein family is known for its regulatory role in apoptosis signaling, making Bcl-2, Mcl-1 and Bcl-xL promising targets. This study evaluates the effects of highly specific inhibitors for Bcl-xL (WEHI-539), Bcl-2 (ABT-199) and Mcl-1 (S63845) as radiosensitizers. Covering a broad spectrum of solid tumors, Non-Small-Cell Lung Cancer (NSCLC), Head and Neck Squamous Cell Carcinoma (HNSCC) and synovial sarcoma cell lines were exposed to fractionated radiation as standard therapy with or without Bcl-2 protein inhibition. Protein expression was detected by Western blot and cell death was assessed by flow cytometry measuring apoptosis. In contrast to NSCLC, a high level of Bcl-xL and its upregulation during radiotherapy indicated radioresistance in HNSCC and synovial sarcoma. Radioresistant cell lines across all entities benefited synergistically from combined therapy with Bcl-xL inhibition and fractionated radiation. In NSCLC cell lines, Mcl-1 inhibition significantly augmented radiotherapy independent of the expression level. Our data suggest that among antiapoptotic Bcl-2 proteins, targeting Bcl-xL may break resistance to radiation in HNSCC, synovial sarcoma and NSCLC in vitro. In NSCLC, Mcl-1 might be a promising target that needs further investigation.

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“…The prototypic and broad BH3-mimetic ABT-737 inhibits BCL-2, BCL-W, and BCL-X L and induces cell death in various tumors including HCC, which highly express BCL-X L [ 20 , 21 ]. Therefore, ABT-737 or the orally available version ABT-263 might be more effective in BCL-X L -expressing tumors, e.g., HCC, compared to ABT-199, which more specifically inhibits BCL-2 [ 22 – 26 ].…”

Section: Introductionmentioning

confidence: 99%

BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment

et al. 2021

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Hepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC patients. Tyrosine-kinase inhibitors (TKI) such as sorafenib represent an alternative treatment option but have only modest efficacy. Using different HCC cell lines and HCC tissues from various patients reflecting HCC heterogeneity, we investigated whether the sorafenib response could be enhanced by combination with pro-apoptotic agents, such as TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737, which target the death receptor and mitochondrial pathway of apoptosis, respectively. We found that both agents could enhance sorafenib-induced cell death which was, however, dependent on specific BH3-only proteins. TRAIL augmented sorafenib-induced cell death only in NOXA-expressing HCC cells, whereas ABT-737 enhanced the sorafenib response also in NOXA-deficient cells. ABT-737, however, failed to augment sorafenib cytotoxicity in the absence of BIM, even when NOXA was strongly expressed. In the presence of NOXA, BIM-deficient HCC cells could be in turn strongly sensitized for cell death induction by the combination of sorafenib with TRAIL. Accordingly, HCC tissues sensitive to apoptosis induction by sorafenib and TRAIL revealed enhanced NOXA expression compared to HCC tissues resistant to this treatment combination. Thus, our results suggest that BH3-only protein expression determines the treatment response of HCC to different sorafenib-based drug combinations. Individual profiling of BH3-only protein expression might therefore assist patient stratification to certain TKI-based HCC therapies.

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Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer

Cited by 27 publications

References 56 publications

Transcript-Level Dysregulation of BCL2 Family Genes in Acute Myeloblastic Leukemia

Transcript-Level Dysregulation of BCL2 Family Genes in Acute Myeloblastic Leukemia

Specific Targeting of Antiapoptotic Bcl-2 Proteins as a Radiosensitizing Approach in Solid Tumors

BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment

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