Pituitary adenomas evade apoptosis via noxa deregulation in Cushing’s disease

Asuzu, David T.; Alvarez, Reinier; Fletcher, Patrick A.; Mandal, Debjani; Johnson, Kory R.; Wu, Weiwei; Elkahloun, Abdel G.; Clavijo, Paúl E.; Allen, Clint; Maric, Dragan; Ray‐Chaudhury, Abhik; Rajan, Sharika; Abdullaev, Zied; Nwokoye, Diana; Aldape, Kenneth; Nieman, Lynnette K.; Stratakis, Constantine A.; Stojilković, Stanko S.; Chittiboina, Prashant

doi:10.1016/j.celrep.2022.111223

Cited by 8 publications

(12 citation statements)

References 95 publications

(121 reference statements)

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“…Cells in APGs were first classified based on the expression of classical marker genes. 17 , 20 , 26 , 32 The expression percentage of each marker gene in the given cell type is annotated in parentheses. Endothelial cells were identified by specific expression of PLVAP (92.3%), ESAM (86.5%), PECAM1 (80.8%), CLEC14A (84.6%), EMCN (90.4%), FLT1 (84.6%), ADGRL4 (84.6%), CAVIN2 (94.2%) or KDR (84.6%); fibroblasts were identified by COL1A1 (95.2%), COL1A2 (100%), COL3A1 (95.2%), COL5A1 (100%), DCN (95.2%), LUM (95.2%), ACTA2 (90.5%), FN1 (95.2%) or FBLN1 (95.2%); lymphocytes were identified by PTPRC (86.0%), CD3E (82.2%), CD3D (70.1%), CD52 (81.3%) or CD48 (85.0%); Myeloid cells were identified by FCER1G (97.8%), CD68 (89.6%), CD14 (80.8%), CD74 (99.5%), RGS1 (87.4%), CSF1R (81.9%), C1QA (84.1%), C1QB (80.8%) or C1QC (81.9%).…”

Section: Methodsmentioning

confidence: 99%

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Single-cell sequencing identifies differentiation-related markers for molecular classification and recurrence prediction of PitNET

Zhang¹,

Yao²,

Long³

et al. 2023

Cell Reports Medicine

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Section: Methodsmentioning

confidence: 99%

“… 30 , 31 One recent publication elaborated in detail on the apoptosis-evading mechanisms in ACTH PitNETs. 32 Despite these studies, an in-depth exploration combining APG and PitNET data to identify tumor origin and differentiation status at single-cell resolution is highly required.…”

Section: Introductionmentioning

confidence: 99%

Single-cell sequencing identifies differentiation-related markers for molecular classification and recurrence prediction of PitNET

Zhang¹,

Yao²,

Long³

et al. 2023

Cell Reports Medicine

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“…In mantle cell lymphoma (MCL) cell lines, despite high NOXA transcript levels, low NOXA protein expression is observed due to rapid protein degradation 41 . Similarly, paradoxical downregulation of NOXA protein is observed in Cushing's disease (CD) adenomas, despite transcriptional upregulation caused by recurrent promoter hypomethylation 42 . These observations suggest that certain showing that UBE2F, in conjunction with RBX2, induces CUL5 neddylation, leading to CRL5 E3 activation and subsequent NOXA degradation 28 .…”

Section: Discussionmentioning

confidence: 99%

Disruption of WSB2-mediated NOXA Degradation Induces Synthetic Lethality to Anti-apoptotic BCL-2 Family Protein Inhibitors

Jiao,

Chang,

Chen

et al. 2024

Preprint

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Anti-apoptotic BCL-2 family proteins are frequently overexpressed in various cancers, contributing to the initiation and development of cancer, as well as intrinsic or acquired resistance to therapy. Although BCL-2 family protein inhibitors, such as Venetoclax, have demonstrated efficacy in hematological neoplasms, their effectiveness as single agents in solid tumors is limited. Identifying alternative molecular targets that can overcome intrinsic resistance to BCL-2 family protein inhibitors is of great clinical importance. Here, we present evidence of strong synthetic lethal interactions between WSB2, a relatively unexplored substrate-binding receptor of the Cullin 5-RBX2-Elongin B/C (CRL5) E3 ubiquitin ligase complex, and multiple anti-apoptotic BCL-2 family proteins. Mechanistically, an assembled CRL5WSB2E3 ubiquitin ligase complex targets NOXA, a pro-apoptotic BCL-2 family protein, for degradation via the ubiquitin-proteasomal pathway. Ablation of WSB2 leads to a remarkable accumulation of NOXA proteins in cultured cell lines and knockout mouse organs. While WSB2 deficiency alone has a minimal effect on spontaneous apoptosis, it renders cancer cells more susceptible to apoptosis when anti-apoptotic BCL-2 family proteins are genetically depleted or pharmacologically inhibited. These findings establish WSB2 as a critical regulator of mitochondrial apoptosis and highlight the dysregulation of the WSB2-NOXA regulatory axis as a contributing factor to apoptosis resistance in cancer cells. Synergistically targeting WSB2 and anti-apoptotic BCL-2 family proteins holds promising clinical potential in the treatment of human cancers.

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“…Our screening included 2480 bioactive compounds, covering a broader range of drugs, thus allowing us to explore various classes (43). Some of the hit compounds listed in Table 1 and Supplementary Table 1 have been validated in terms of their potent efficacy against ACTH-secreting PitNETs; these include HDAC inhibitors (18–21), HSP90 inhibitors (22–24), PI3K inhibitors (18), proteasome inhibitors (25), an adrenergic receptor antagonist (44), and epidermal growth factor receptor inhibitors (45, 46). These results support the relevancy of our HTS results in terms of identifying therapeutic agents for Cushing’s disease.…”

Section: Discussionmentioning

confidence: 99%

“…Among the 20 compounds with significant effects at 1 μM, histone deacetylase (HDAC) inhibitors (18)(19)(20)(21), heat shock protein 90 (HSP90) inhibitors (22)(23)(24), phosphatidylinositol-3 kinase (PI3K) inhibitors (18), and proteasome inhibitors (25) have been reported to have antitumor effects against ACTH-secreting PitNETs. After excluding the compounds belonging to these classes, we focused on TS, a natural compound containing a thiazole ring.…”

Section: Verification Of Ts Effects On Att-20 Cellsmentioning

confidence: 99%

High-throughput screening for Cushing’s disease: therapeutic potential of thiostrepton via cell cycle regulation

Hakata,

Yamauchi,

Kosugi

et al. 2024

Preprint

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Cushing’s disease is a life-threatening disorder caused by autonomous secretion of adrenocorticotropic hormone (ACTH) from pituitary neuroendocrine tumors (PitNETs). Few drugs are indicated for inoperative Cushing’s disease, in particular that due to aggressive PitNETs. To explore agents that regulate ACTH-secreting PitNETs, we conducted high-throughput screening (HTS) using AtT-20, a murine pituitary tumor cell line characterized by ACTH secretion. For the HTS, we constructed a live cell– based ACTH reporter assay for high-throughput evaluation of ACTH changes. This assay was based on HEK293T cells overexpressing components of the ACTH receptor and a fluorescent cAMP biosensor, with high-throughput acquisition of fluorescence images at the single-cell level. Of 2480 screened bioactive compounds, over 50% inhibition of ACTH secreted from AtT-20 cells was seen with 84 compounds at 10 μM, and 20 compounds at 1 μM. Among these hit compounds, we focused on thiostrepton (TS) and determined its antitumor effects in bothin vitroandin vivoxenograft models of Cushing’s disease. Transcriptome and flow cytometry analyses revealed that TS administration induced AtT-20 cell cycle arrest at the G2/M phase, which was mediated by FOXM1-independent mechanisms including downregulation of cyclins. Simultaneous TS administration with a CDK 4/6 inhibitor that affected the cell cycle at the G0/1 phase showed cooperative antitumor effects. Thus, TS is a promising therapeutic agent for Cushing’s disease. Our list of hit compounds and new mechanistic insights into TS effects serve as a valuable foundation for future research.

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Pituitary adenomas evade apoptosis via noxa deregulation in Cushing’s disease

Cited by 8 publications

References 95 publications

Single-cell sequencing identifies differentiation-related markers for molecular classification and recurrence prediction of PitNET

Single-cell sequencing identifies differentiation-related markers for molecular classification and recurrence prediction of PitNET

Disruption of WSB2-mediated NOXA Degradation Induces Synthetic Lethality to Anti-apoptotic BCL-2 Family Protein Inhibitors

High-throughput screening for Cushing’s disease: therapeutic potential of thiostrepton via cell cycle regulation

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