A NOXA/MCL‐1 Imbalance Underlies Chemoresistance of Malignant Rhabdoid Tumor Cells

Ouchi, Kazutaka; Kuwahara, Yasumichi; Iehara, Tomoko; Miyachi, Mitsuru; Katsumi, Yoshiki; Tsuchiya, Kunihiko; Konishi, Eiichi; Yanagisawa, Akio; Hosoi, Hajime

doi:10.1002/jcp.25293

Cited by 12 publications

(15 citation statements)

References 35 publications

(44 reference statements)

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“…In this mimicry study by Fang et al., a single diastereomer of a macrolactam core (Compound 7, PDB ID: 4WGI) was reported as a direct, NOXA BH3 competitive, MCL‐1 inhibitor . The interplay between NOXA and MCL‐1 expression has also recently been proposed to regulate chemoresistance of malignant rhabdoid tumor cells . Overall, current knowledge directly attains an influential role for NOXA to be used as a highly selective, intrinsic MCL‐1 inhibitor.…”

Section: Mcl‐1 Inhibitorsmentioning

confidence: 99%

Selective targeting of antiapoptotic BCL‐2 proteins in cancer

Timuçin

Başağa

Kütük

2018

Medicinal Research Reviews

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Circumvention of apoptotic machinery is one of the distinctive properties of carcinogenesis. Extensively established key effectors of such apoptotic bypass mechanisms, the antiapoptotic BCL-2 (apoptosis regulator BCL-2) proteins, determine the response of cancer cells to chemotherapeutics. Within this background, research and development of antiapoptotic BCL-2 inhibitors were considered to have a tremendous amount of potential toward the discovery of novel pharmacological modulators in cancer. In this review, milestone achievements in the development of selective antiapoptotic BCL-2 proteins inhibitors for BCL-2, BCL-XL (BCL-2-like protein 1), and MCL-1 (induced myeloid leukemia cell differentiation protein MCL-1) were summarized and their future implications were discussed. In the first section, the design and development of BCL-2/BCL-XL dual inhibitor navitoclax, as well as the recent advances and clinical experience with selective BCL-2 inhibitor venetoclax, were synopsized. Preclinical data from selective BCL-XL inhibitors, which are currently undergoing extensive testing as a single agent or in combination with other therapeutic agents, were further summarized. In the second section, MCL-1 inhibitors developed as potential anticancer agents were reviewed regarding their specificity toward MCL-1. Explicitly, studies leading to the identification of MCL-1, nonselective and selective targeting of MCL-1, and recently initiated clinical trials were compiled in chronological order. Based on these concepts, future directions were further discussed for increasing selectivity in the design of prosurvival BCL-2 member inhibitors.

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Section: Mcl‐1 Inhibitorsmentioning

confidence: 99%

Selective targeting of antiapoptotic BCL‐2 proteins in cancer

Timuçin

Başağa

Kütük

2018

Medicinal Research Reviews

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“…immunohistochemical analysis of clinical samples we used the automated Ventana Benchmark Ultra platform (Roche, Basel, Switzerland) as described previously (34). The sections were immuno-stained with i) vimentin (1:400, M7020, DAKO Denmark A/S, Glostrup, Denmark), ii) epithelial membrane antigen (1:200, M0613, DAKO), iii) smooth muscle actin (1:2,000, A2547, Sigma-Aldrich, St. Louis, MO, USA), iv) cytokeratin 8 (1:100, NCL-L-CK8-TS1, Leica Biosystems Inc., Lincolnshire, IL, USA), v) cytokeratin AE1/AE3 (1:100, NCL-L-AE1/AE3, Leica Biosystems), vi) desmin (1:100, M0760, DAKO), vii) S100 (1:2,000, Z0311, DAKO), viii) GFAP (1:2,000, N1506, DAKO), or ix) SNF5 (1:2,000, ab58209, Abcam, Cambridge, UK).…”

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confidence: 99%

Novel Two MRT Cell Lines Established from Multiple Sites of a Synchronous MRT Patient

et al. 2020

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“…24 Therefore, the Noxa/Mcl1 balance and the regulation of the Noxa/Mcl1 axis are important for the sensitivity to drug-induced apoptosis. 25 There has been an extensive effort and search over the last years for diagnostic, prognostic and predictive biomarkers in CRC, including our recent study on DR5 and apoptotic gene signature, 26 since early detection and prevention of disease progression are critical. In this study, the mRNA expression profile of Noxa and Mcl1 genes was investigated in human colorectal adenocarcinoma cell lines, as well as in CRC and normal tissue samples, in order to evaluate their significance and putative association with KRAS mutation status and clinic-pathological features in CRC Noxa and Mcl1 in association with DR5, cIAP1 and cIAP2 apoptotic gene expression were also evaluated for their discriminatory value between CRC and normal colorectal tissue.…”

Section: Introductionmentioning

confidence: 99%

Noxa upregulation and 5‐gene apoptotic biomarker panel in colorectal cancer

Kosmidou

Vlassi

Anagiotos

et al. 2020

Eur J Clin Investigation

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Background NOXA and MCL1 are involved in the intrinsic pathway of apoptosis, where Noxa selectively binds to MCL1 and prevents it from inhibiting apoptosis. Both factors are considered as potential tumour biomarkers, while MCL1 has attracted interest as target in cancer. The purpose of this study was to investigate the expression of NOXA and MCL1 in 160 CRC tumour samples, to investigate their significance, also in combination with IAPs, DR5 expression and KRAS gene mutations in CRC. Materials and methods Fresh frozen colorectal tissue was obtained from patients undergoing surgery for CRC. Real‐time quantitative PCR was performed for the determination of mRNA expression levels. Protein expression was determined immunohistochemically. Differences in the mRNA expression profile were evaluated with the nonparametric Wilcoxon signed ranks test. Statistical analysis was performed with the use of Mann‐Whitney U test and receiver‐operating characteristic (ROC) curve. Results NOXA was found to be overexpressed in CRC tumours (P < .0001), even from early stage. Moreover, NOXA/MCL1 mRNA expression was significantly elevated in tumour samples compared to normal pairs (P < .0001). ROC curve analysis showed that both NOXA expression and its combination with Mcl1 expression have fair discriminatory value between CRC and normal colorectal tissue. Combinatorial ROC analysis revealed the most significant discriminatory value of NOXA, MCL1 with cIAP1 and cIAP2 (AUC = 0.834, P < .0001) as a 5‐gene panel of markers. Conclusion Noxa, Mcl1, DR5, cIAP1 and cIAP2 mRNA expressions are significantly deregulated in CRC and could provide a panel of markers with significant discriminatory value between CRC and normal colorectal tissue.

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A NOXA/MCL‐1 Imbalance Underlies Chemoresistance of Malignant Rhabdoid Tumor Cells

Cited by 12 publications

References 35 publications

Selective targeting of antiapoptotic BCL‐2 proteins in cancer

Selective targeting of antiapoptotic BCL‐2 proteins in cancer

Novel Two MRT Cell Lines Established from Multiple Sites of a Synchronous MRT Patient

Noxa upregulation and 5‐gene apoptotic biomarker panel in colorectal cancer

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