STMN1 is Overexpressed in Adrenocortical Carcinoma and Promotes a More Aggressive Phenotype In Vitro

Aronova, Anna; Min, Irene M.; Crowley, Michael J.; Panjwani, Suraj; Finnerty, Brendan M.; Scognamiglio, Theresa; Liu, Yifang; Whitsett, Timothy G.; Garg, Shipra; Demeure, Michael J.; Elemento, Olivier; Zarnegar, Rasa; Fahey, Thomas J.

doi:10.1245/s10434-017-6296-2

Cited by 16 publications

(12 citation statements)

References 31 publications

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“…Alterations in the expression of β-tubulin isotypes and apoptotic regulatory proteins such as XIAP and MAPs (microtubule-associated proteins) regulated PTX activity in different types of cancers 12 , 15 , 20 , 30 . For example, drug-resistant cancer cells and human tumor tissues were shown to harbor tubulin gene mutations, alterations in total tubulin content, altered microtubule polymer levels, altered expression of tubulin isotypes, and altered microtubule-associated protein expression 13 , 14 , 21 , 28 , 30 . High expression of βIII-tubulin has been found to be correlated either with low response rates in patients treated with regimens containing taxanes or vinorelbine or with reduced survival in patients with NSCLC, breast, ovarian, and gastric cancers 40 .…”

Section: Discussionmentioning

confidence: 99%

“…The degradation was a proteasome-dependent, rapid and irreversible process initiated by tubulin aggregation 24 . Some studies showed that XIAP, Tau, Hsp70 partly were degraded by 26S proteasome 25 – 28 . Here SFN-Cys and SFN-NAC induced the degradation of XIAP, Tau, Hsp70, Stathmin1 via upregulating 26S proteasome, and the effects of degradation were reversed by 26S proteasome inhibitor MG132.…”

Section: Discussionmentioning

confidence: 99%

“…The level of XIAP was regulated depending on activation of the 26S proteasome 25 . Hsp70 and Stathmin1 could be cleaved dependent of ubiquitination and degradation by 26S proteasome; misfolded and aggregated Tau can be degraded by enhancement of proteasomal activity in neurons 23 , 26 – 28 . Just recently, we found that SFN metabolites disrupted microtubules and incredibly induced apoptosis via ERK1/2 phosphorylation, downregulation of α-tubulin, microtubule associated proteins, such as Stathmin1, etc.…”

Section: Introductionmentioning

confidence: 99%

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Sulforaphane metabolites reduce resistance to paclitaxel via microtubule disruption

et al. 2018

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Long treatment with paclitaxel (PTX) might increase resistance and side-effects causing a failure in cancer chemotherapy. Here we uncovered that either sulforaphane-cysteine (SFN-Cys) or sulforaphane-N-acetyl-cysteine (SFN-NAC) induced apoptosis via phosphorylated ERK1/2-mediated upregulation of 26 S proteasome and Hsp70, and downregulation of βIII-tubulin, XIAP, Tau, Stathmin1 and α-tubulin causing microtubule disruption in human PTX-resistant non-small cell lung cancer (NSCLC) cells. Knockdown of either βIII-tubulin or α-tubulin via siRNA increased cell sensitivity to PTX, indicating that these two proteins help cells increase the resistance. Tissue microarray analysis showed that overexpression of βIII-tubulin correlated to NSCLC malignant grading. Immunofluorescence staining also showed that SFN metabolites induced a nest-like microtubule protein distribution with aggregation and disruption. Co-immunoprecipitation showed that SFN metabolites reduced the interaction between βIII-tubulin and Tau, and that between α-tubulin and XIAP. The combination of PTX with SFN metabolites decreased the resistance to PTX, and doses of both PTX and SFN metabolites, and enhanced apoptosis resulting from activated Caspase-3-caused microtubule degradation. Importantly, the effective dose of SFN metabolites combined with 20 nM PTX will be low to 4 μM. Thus, we might combine SFN metabolites with PTX for preclinical trial. Normally, more than 20 μM SFN metabolites only leading to apoptosis for SFN metabolites hindered their applications. These findings will help us develop a low-resistance and high-efficiency chemotherapy via PTX/SFN metabolites combination.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sulforaphane metabolites reduce resistance to paclitaxel via microtubule disruption

et al. 2018

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“…During the mitotic interval, the active state of STMN1 protein promotes microtubule depolymerization. 17 The expression level of STMN1 in tumors is directly related to the prognosis of patients, and the expression of stathmin protein in tumor cells affects the sensitivity of vinblastine and paclitaxel drugs. 18 Based on the above evidence, LINC01116 plays a critical role in tumor development.…”

Section: Introductionmentioning

confidence: 99%

<p>LncRNA LINC01116 Promotes the Development of Colorectal Cancer by Targeting miR-9-5p/STMN1</p>

Bi¹,

Cui²,

Fan³

et al. 2020

OTT

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The aim was to research the role of LINC01116 in the prognosis of colorectal cancer (CRC) patients and development of colorectal cancer cells. Methods: In total 62 colorectal cancer patient tissues and human CRC cell lines (OUMS23, SW116, SW480 and LOVO) were obtained for this study. SiLINC01116, miR-9-5p mimic, LINC01116, oe-STMN1 and their controls were transfected. The qRT-PCR method and Western blot were used to detect the levels of LINC01116, miR-9-5p and STMN1 in tissues and cells. CCK8 assay and flow cytometry were processed for proliferation and apoptosis, respectively. Transwell assay was undertaken to verify invasion and migration. Luciferase assay and pull down assay were processed to confirm the binding relationship among LINC01116, miR-9-5p and STMN1. Immunohistochemistry assay also detected the expression of STMN1. Kaplan-Meier survival curve was used to analyze patient survival rate. Pearson correlation analysis was used to evaluate the regulatory relationship between LINC01116, miR-9-5p and STMN1 in tissues. Results: LINC01116 was expressed higher in CRC tissues and cells. Patients with higher expression of LINC01116 had worse prognosis. Knockdown of LINC01116 suppressed development of CRC cell. LINC01116 negatively regulated miR-9-5p, while MiR-9-5p was negatively related to STMN1. miR-9-5p mimic could rescue the effect of LINC01116, inhibit migration and invasion, and improve apoptosis of CRC cells. Oe-STMN1 could also rescue the effect of miR-9-5p on the development of colorectal cancer. Conclusion: LINC01116 promoted the development of colorectal cancer via modulating miR-9-5p/STMN1 axis.

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“…Somatically, dysregulation of protein kinase A and mutations in ADIPOR1 , ADIPOR2 , APC , ARMC5 , SDHA , SDHC , SF1 , and IGF2 , among others, have also been implicated as mediators of ACC tumorigenesis, along with mutations in RB1 and APC (Babińska et al 2017; Else et al 2017). Recent expression studies have identified sonic hedgehog and somatostatin receptor pathways activated in ACC, along with markedly increased expression in cytosolic protein Stathmin1, SLC12A7 and phospho-mTOR, EGFR, and WNT/β-catenin signaling pathways (Germano et al 2017; Aronova et al 2018; Brown et al 2018a,b; Hasanovic et al 2018). At the miRNA level, miR-483-3p and miR-139-5p promote ACC aggressiveness (Agosta et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Genomic stratification and liquid biopsy in a rare adrenocortical carcinoma (ACC) case, with dual lung metastases

McCabe

Pinese

Chan

et al. 2019

Cold Spring Harb Mol Case Stud

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Adrenocortical carcinoma is a rare malignancy with a poor prognosis and few treatment options. Molecular characterization of this cancer remains limited. We present a case of an adrenocortical carcinoma (ACC) in a 37-yr-old female, with dual lung metastases identified 1 yr following commencement of adjuvant mitotane therapy. As standard therapeutic regimens are often unsuccessful in ACC, we undertook a comprehensive genomic study into this case to identify treatment options and monitor disease progress. We performed targeted and whole-genome sequencing of germline, primary tumor, and both metastatic tumors from this patient and monitored recurrence over 2 years using liquid biopsy for ctDNA and steroid hormone measurements. Sequencing revealed the primary and metastatic tumors were hyperhaploid, with extensive loss of heterozygosity but few structural rearrangements. Loss-of-function mutations were identified in MSH2 , TP53 , RB1 , and PTEN , resulting in tumors with mismatch repair signatures and microsatellite instability. At the cellular level, tumors were populated by mitochondria-rich oncocytes. Longitudinal ctDNA mutation and hormone profiles were unable to detect micrometastatic disease, consistent with clinical indicators of disease remission. The molecular signatures in our ACC case suggested immunotherapy in the event of disease progression; however, the patient remains free of cancer. The extensive molecular analysis presented here could be applied to other rare and/or poorly stratified cancers to identify novel or repurpose existing therapeutic options, thereby broadly improving diagnoses, treatments, and prognoses.

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STMN1 is Overexpressed in Adrenocortical Carcinoma and Promotes a More Aggressive Phenotype In Vitro

Cited by 16 publications

References 31 publications

Sulforaphane metabolites reduce resistance to paclitaxel via microtubule disruption

Sulforaphane metabolites reduce resistance to paclitaxel via microtubule disruption

<p>LncRNA LINC01116 Promotes the Development of Colorectal Cancer by Targeting miR-9-5p/STMN1</p>

Genomic stratification and liquid biopsy in a rare adrenocortical carcinoma (ACC) case, with dual lung metastases

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