Unbiased Proteomic and Transcript Analyses Reveal that Stathmin-1 Silencing Inhibits Colorectal Cancer Metastasis and Sensitizes to 5-Fluorouracil Treatment

Wu, Wei; Tan, Xing Fei; Tan, Hwee Hoon; Lim, Teck Kwang; Chung, Maxey C. M.

doi:10.1158/1541-7786.mcr-14-0088-t

Cited by 25 publications

(30 citation statements)

References 27 publications

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“…The inhibition of STMN1 reduced cell proliferation over the first 24 hours but not by 48 hours, and reducing STMN1 had no effect on MPM cell clonogenicity. However, inhibiting STMN1 reduced MPM cell motility, supporting earlier studies in gastric (17) and colon cancers (48).…”

Section: Discussionsupporting

confidence: 87%

Loss of miR-223 and JNK Signaling Contribute to Elevated Stathmin in Malignant Pleural Mesothelioma

Birnie

Yip

et al. 2015

Molecular Cancer Research

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Malignant pleural mesothelioma (MPM) is often fatal, and studies have revealed that aberrant miRNAs contribute to MPM development and aggressiveness. Here, a screen of miRNAs identified reduced levels of miR-223 in MPM patient specimens. Interestingly, miR-223 targets Stathmin (STMN1), a microtubule regulator that has been associated with MPM. However, whether miR-223 regulates STMN1 in MPM and the functions of miR-223 and STMN1 in this disease are yet to be determined. STMN1 is also regulated by c-Jun N-terminal kinase (JNK) signaling, but whether this occurs in MPM and whether miR-223 plays a role are unknown. The relationship between STMN1, miR-223, and JNK was assessed using MPM cell lines, cells from pleural effusions, and MPM tissue. Evidence indicates that miR-223 is decreased in all MPM tissue compared with normal/healthy tissue. Conversely, STMN1 expression was higher in MPM cell lines when compared with primary mesothelial cell controls. Following overexpression of miR-223 in MPM cell lines, STMN1 levels were reduced, cell motility was inhibited, and tubulin acetylation induced. Knockdown of STMN1 using siRNAs led to inhibition of MPM cell proliferation and motility. Finally, miR-223 levels increased while STMN1 was reduced following the re-expression of the JNK isoforms in JNK-null murine embryonic fibroblasts, and STMN1 was reduced in MPM cell lines following the activation of JNK signaling.Implications: miR-223 regulates STMN1 in MPM, and both are in turn regulated by the JNK signaling pathway. As such, miR-223 and STMN1 play an important role in regulating MPM cell motility and may be therapeutic targets.

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Section: Discussionsupporting

confidence: 87%

Loss of miR-223 and JNK Signaling Contribute to Elevated Stathmin in Malignant Pleural Mesothelioma

Birnie

Yip

et al. 2015

Molecular Cancer Research

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“…17 Inhibition of STMN1 with small interfering RNA (siRNA) was shown to sensitize cancer cells to 5-FU treatment. 18 However the synergistic effects between 5-FU were question in studies of antistathmin ribozyme with 5-FU or adriamycin, in which both were shown to be additive. 19 Additionally, knockdown of STMN1 blocked tumor growth in vivo in a model of pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Novel indolyl-chalcones target stathmin to induce cancer cell death

Węgiel

Jernigan

et al. 2016

Cell Cycle

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Efficacy of current therapies for advanced and metastatic cancers remains a challenge in clinical practice. We investigated the anti-cancer potency of 3 novel indoly-chalcones (CITs). Our results indicated the lead molecule CIT-026 (Formula D C 20 H 16 FNO) induced cell death in prostate and lung cancer cell lines at sub-micromolar concentration. CITs (CIT-026, CIT-214, CIT-223) lead to microtubule destabilization, cell death and low cell proliferation, which in part was dependent on stathmin (STMN1) expression. Knockdown of STMN1 with siRNA against STMN1 in part restored viability of cancer cells in response to CITs. Further, CIT-026 and CIT-223 blocked cancer cell invasion through matrigel-coated chambers. Mechanistically, CITs inhibited phosphorylation of STMN1 leading to STMN1 accumulation and mitotic catastrophe. In summary, we have synthetized novel anti-cancer CIT molecules and defined their mechanism of action in vitro.

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“…Chemoresistance to docetaxel with stathmin overexpression may be caused by the microtubule‐destabilizing activity of stathmin, which may diminish binding to docetaxel and increase binding to vincristine‐like drugs . Chemoresistance to cisplatin and 5‐fluorouracil with stathmin overexpression may be caused by the participation of stathmin overexpression in the cellular response to DNA damage and caspase‐6‐mediated cellular apoptosis, as described in previous studies conducted in head and neck cancer or colorectal cancer, respectively . To some extent, these reasons lead to the unsatisfactory clinical benefit of TPF induction chemotherapy in OSCC patients with high stathmin expression.…”

Section: Discussionmentioning

confidence: 93%

Stathmin guides personalized therapy in oral squamous cell carcinoma

Long

Zhao

et al. 2020

Cancer Science

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The survival benefit from docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy in oral squamous cell carcinoma (OSCC) patients is not satisfactory.Previously, we identified that stathmin, a microtubule-destabilizing protein, is overexpressed in OSCC. Here, we further investigated its role as a biomarker that impacts on OSCC chemosensitivity. We analyzed the predictive value of stathmin on TPF induction chemotherapy and its impact on OSCC cell chemosensitivity. Then, we further investigated the therapeutic effects of the combination therapy of TPF chemotherapy and PI3K-AKT-mTOR inhibitors in vitro and in vivo. We found that OSCC patients with low stathmin expression benefited from TPF induction chemotherapy, while OSCC patients with high stathmin expression could not benefit from TPF induction chemotherapy. Stathmin overexpression promoted cellular proliferation and decreased OSCC cell sensitivity to TPF treatment. In addition, inhibition of the PI3K-AKT-mTOR signaling pathway decreased stathmin expression and phosphorylation.The combination therapy of TPF chemotherapy and PI3K-AKT-mTOR inhibitors exhibited a potent antitumor effect both in vitro and in vivo. Therefore, stathmin can be used as a predictive biomarker for TPF induction chemotherapy and a combination therapy regimen based on stathmin expression might improve the survival of OSCC patients. K E Y W O R D Sbiomarker, induction chemotherapy, oral squamous cell carcinoma, personalized therapy, translational medicine

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Unbiased Proteomic and Transcript Analyses Reveal that Stathmin-1 Silencing Inhibits Colorectal Cancer Metastasis and Sensitizes to 5-Fluorouracil Treatment

Cited by 25 publications

References 27 publications

Loss of miR-223 and JNK Signaling Contribute to Elevated Stathmin in Malignant Pleural Mesothelioma

Loss of miR-223 and JNK Signaling Contribute to Elevated Stathmin in Malignant Pleural Mesothelioma

Novel indolyl-chalcones target stathmin to induce cancer cell death

Stathmin guides personalized therapy in oral squamous cell carcinoma

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