Nitidine chloride represses Mcl‐1 protein via lysosomal degradation in oral squamous cell carcinoma

Yang, In‐Hyoung; Jung, Won Seok; Kim, Lee-Han; Shin, Ji‐Ae; Cho, Nam-Pyo; Hong, Seong Doo; Hong, Kyoung‐Ok; Cho, Sung‐Dae

doi:10.1111/jop.12755

Cited by 17 publications

(16 citation statements)

References 29 publications

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“…NC treatment did not have liver or kidney toxicity in mouse model [58]. This group further identified that NC suppressed Mcl-1 protein level via lysosomedependent degradation in oral squamous cell carcinoma [59]. These reports suggest that NC might be a putative agent against oral cancer [58].…”

Section: Other Cancersmentioning

confidence: 80%

Antitumor functions and mechanisms of nitidine chloride in human cancers

Cui¹,

Wu²,

Cao³

et al. 2020

J. Cancer

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Nitidine chloride (NC), a quaternary ammonium alkaloid, exhibits multiple biological activities, including antimalarial, antifungal, and antiangiogenesis. Recently, NC has been characterized to perform antitumor activity in a variety of malignancies. NC has been identified to suppress cell proliferation, stimulate apoptosis, and induce cell cycle arrest, retard migration, invasion and metastasis. Moreover, NC is reported to sensitize cancer cells to chemotherapeutic drugs. In this review article, we describe the functions of NC in human cancers and discuss the molecular insight into NC-involved antitumor feature. This review article will stimulate the deeper investigation for using NC as a potent agent for the management of cancer patients.

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Section: Other Cancersmentioning

confidence: 80%

Antitumor functions and mechanisms of nitidine chloride in human cancers

Cui¹,

Wu²,

Cao³

et al. 2020

J. Cancer

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“…Natural products have been regarded as one of the most promising therapeutic strategies given their abilities to regulate Mcl-1 proteins at the transcriptional, post-transcriptional, and post-translational levels (35). Our previous findings have demonstrated that bioactive compounds derived from natural products serve as apoptosis-inducing agents via modulating the protein stability of Mcl-1 (17,36) Based on our observations, the results revealed an unexpected phenomenon in which EEJS-induced mitotic catastrophe was insufficient to induce apoptotic cell death in HSC-4 cells only. Based on this result, we speculate that EEJS may enable HSC-4 cells to evade apoptotic cell death due to the maintenance of Mcl-1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…The Mcl-1 overexpression vector was constructed as described previously (17). The HSC-3 cells were transfected with either 1 µg of empty pcDNA3.1 or pcDNA3.1-Mcl-1 using Lipofectamine ® 2000 (Thermo Fisher Scientific, Inc.) according to the manufacturer's instructions.…”

Section: Construction Of Mcl-1 Overexpression Vector and Transient Tr...mentioning

confidence: 99%

In vitro induction of mitotic catastrophe as a therapeutic approach for oral cancer using the ethanolic extract of Juniperus squamata

et al. 2021

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Mitotic catastrophe, a cell death mechanism characterized by abnormal mitosis, has been regarded as a therapeutic approach for the development of anti-cancer drug candidates. The aim of the present study was to investigate the potential effect of the ethanolic extract of Juniperus squamata (EEJS) on the occurrence of mitotic catastrophe in human oral cancer cell lines. The effect of EEJS on the occurrence of mitotic catastrophe was evaluated by measuring cytotoxicity, observing phase-contrast or transmission electron microscope findings, evaluating the appearance of microtubule or chromosome abnormalities, and detecting the phosphorylation of histone H3 (Ser 10 ). The apoptotic effect of EEJS was assessed by detecting cleaved PARP, analyzing the sub-G 1 population, Annexin V-FITC/PI double staining, western blot analysis, and the transient transfection of myeloid cell leukemia-1 (Mcl-1) overexpression vectors. EEJS treatment was effective in inhibiting cell proliferation in human oral cancer cell lines. EEJS resulted in the enrichment of enlarged multinucleated cells, the disturbance of microtubule formation, and increased phosphorylation of histone H3 (Ser 10 ), which demonstrates the occurrence of mitotic catastrophe. Additionally, the multinucleated cells underwent apoptotic cell death in a cell context-dependent manner, which was associated with the reduction of Mcl-1 protein levels. Findings of the present study indicate that EEJS could be effective for treating human oral cancer by promoting mitotic catastrophe linked to apoptotic cell death.

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“…Reportedly, the posttranslational modification of Mcl-1 is accompanied by ubiquitination, cleavage, and phosphorylation, which decides the protein turnover, localization, and function [ 22 ]. In particular, our previous findings have shown that Mcl-1 inhibition induced by naturally occurring compounds in oral cancer cells is involved in lysosome- or proteasome-dependent degradation [ 23 , 24 ]. These results led us to speculate that EEPK may cause a rapid turnover of Mcl-1 protein in human MEC cells.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism underlying the apoptotic modulation by ethanol extract of Pseudolarix kaempferi in mucoepidermoid carcinoma of the salivary glands

et al. 2021

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Background Pseudolarix kaempferi is a traditional Chinese natural product that possesses the potential cytotoxic effects against cancer. However, the precise molecular mechanism underlying its cytotoxic effects has not yet been completely elucidated. Here, we clarify the mechanism via which the ethanol extract of P. kaempferi (EEPK) leads to cytotoxicity mediated by apoptosis in mucoepidermoid carcinoma (MEC) originating from the salivary glands. Methods We investigated the mechanism underlying the anticancer efficacy of EEPK in human MEC in vitro by assessing mitochondrial dysfunction, mRNA levels, and morphological changes in apoptotic cell nuclei as well as by using a cytotoxicity assay, flow cytometric analysis, and western blotting. Results EEPK inhibited the growth of two human MEC cells and stimulated the induction of caspase-mediated apoptosis that was accompanied by mitochondrial membrane depolarization. Compared with the vehicle control groups, EEPK decreased myeloid cell leukemia-1 (Mcl-1) expression in both cells whereas it significantly decreased B cell lymphoma-2 (Bcl-2) expression in MC3 cells only. The EEPK-induced altered Mcl-1 expression was caused by translational inhibition and proteasomal degradation. Additionally, EEPK significantly increased p-Bcl-2 (Ser70) expression regardless of its total forms by facilitating the activation of the c-Jun N-terminal kinase (JNK) signaling pathway, which exhibited cell context dependency. Nevertheless, JNK activation following EEPK treatment was, at least in part, required for the proapoptotic efficacy of EEPK in both cells. Conclusions This study revealed that EEPK-induced alterations of Mcl-1 inhibition and JNK/Bcl-2 phosphorylation cause apoptosis and provided basic preclinical data for future clinical trials regarding therapy for patients with MEC. Graphic abstract

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Nitidine chloride represses Mcl‐1 protein via lysosomal degradation in oral squamous cell carcinoma

Abstract: Our findings suggest that NC triggers apoptosis via lysosome-dependent Mcl-1 protein degradation and could be chosen as a promising chemotherapeutic candidate against human OSCCs.

Cited by 17 publications

References 29 publications

Antitumor functions and mechanisms of nitidine chloride in human cancers

Antitumor functions and mechanisms of nitidine chloride in human cancers

In vitro induction of mitotic catastrophe as a therapeutic approach for oral cancer using the ethanolic extract of Juniperus squamata

Molecular mechanism underlying the apoptotic modulation by ethanol extract of Pseudolarix kaempferi in mucoepidermoid carcinoma of the salivary glands

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