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 19 publications

(17 citation statements)

References 56 publications

(65 reference statements)

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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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“…Several studies of pan-cancer analysis have addressed the significance of aberrant expressed genes in the development or progression of CRC. To evaluate the role of antiapoptotic BCL-2 proteins on preclinical CRC models, Scherr et al have found that BCL-XL is overactivated in CRC, which provides a promising therapeutic target for CRC by analyzing a pan-cancer cohort, [ 26 ].High ANKRD6 expression is correlated with poor prognosis of colon cancer based on a pan-cancer analysis, which suggests ANKRD6 plays an important role in the progression of colon cancer [ 27 ]. According to a pan-cancer analysis, RRM2ishighlyexpressed in many cancers, Further experiment has found that RRM2 is significantly upregulated in CRC.RRM2 might serve as a novel potential target for CRC therapy [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer analysis of oncogenic role of Programmed Cell Death 2 Like (PDCD2L) and validation in colorectal cancer

Gao

Liang

et al. 2022

Cancer Cell Int

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Background Programmed Cell Death 2 Like (PDCD2L) correlates with cell proliferation, apoptosis and mouse embryonic development. However, the role of PDCD2L in human cancers is unclear. Methods Multiple bioinformatic methods, in vitro function experiments and validation were performed to clarify the oncogenic role of PDCD2L in human cancers. Results Our study found that PDCD2L was aberrantly expressed in multiple types of human cancers, and associated with clinical stage and molecular subtype. Furthermore, overexpression of PDCD2L predicted poor overall survival in adrenocortical carcinoma(ACC), kidney chromophobe(KICH), acute myeloid leukemia(LAML), brain lower grade glioma(LGG),liver hepatocellular carcinoma(LIHC), mesothelioma(MESO), uveal melanoma(UVM) and poor diseases free survival in ACC, bladder urothelial carcinoma(BLCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), kidney renal clear cell carcinoma(KIRC), kidney renal papillary cell carcinoma(KIRP), LGG, LIHC, and UVM. PDCD2L expression was negatively associated with cancer associated fibroblast in breast invasive carcinoma (BRCA), lung squamous cell carcinoma (LUSC), sarcoma (SARC), stomach adenocarcinoma (STAD) and testicular germ cell tumors (TGCT). Mechanically, we found that PDCD2L expression was associated with apoptosis, invasion and cell cycle by investigating single cell sequencing data. For further validation, PDCD2Lwas highly expressed in colorectal cancer (CRC) cell lines and tissue samples compared with the normal colon cell line and non-tumor adjacent colorectal mucosa tissues. PDCD2L knockdown induced the apoptosis and proliferation of CRC cells. Conclusions Our study shows that the oncogenic role of PDCD2L in various cancers and PDCD2L could be served as a biomarker of CRC.

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

Cited by 19 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

Pan-cancer analysis of oncogenic role of Programmed Cell Death 2 Like (PDCD2L) and validation in colorectal cancer

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