Molecular Comprehension of Mcl-1: From Gene Structure to Cancer Therapy

Senichkin, Viacheslav V; Streletskaia, Alena Y; Zhivotovsky, Boris; Kopeina, Gelina S.

doi:10.1016/j.tcb.2019.03.004

Cited by 77 publications

(64 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mcl-1 is a Bcl-2 family member that suppression the intrinsic apoptotic pathway by modulating mitochondrial integrity 35,36 . Overexpression of Mcl-1 is frequently observed in human cancers, including NSCLC 37 , colorectal 38 , liver 39 , prostate cancer 40 , and multiple myeloma 41 .…”

Section: Discussionmentioning

confidence: 99%

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

Gao

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

Activating mutations of epidermal growth factor receptor (EGFR) play crucial roles in the oncogenesis of human nonsmall cell lung cancer (NSCLC). By screening 79 commercially available natural products, we found that the natural compound deguelin exhibited a profound anti-tumor effect on NSCLC via directly down-regulating of EGFR-signaling pathway. Deguelin potently inhibited in vitro EGFR kinase activity of wild type (WT), exon 19 deletion, and L858R/ T790M-mutated EGFR. The in silico docking study indicated that deguelin was docked into the ATP-binding pocket of EGFRs. By suppression of EGFR signaling, deguelin inhibited anchorage-dependent, and independent growth of NSCLC cell lines, and significantly delayed tumorigenesis in vivo. Further study showed that deguelin inhibited EGFR and downstream kinase Akt, which resulted in the activation of GSK3β and eventually enhanced Mcl-1 phosphorylation at S159. Moreover, deguelin promoted the interaction between Mcl-1 and E3 ligase SCF FBW7 , which enhanced FBW7-mediated Mcl-1 ubiquitination and degradation. Additionally, phosphorylation of Mcl-1 by GSK3β is a prerequisite for FBW7-mediated Mcl-1 destruction. Depletion or pharmacological inactivation of GSK3β compromised deguelin-induced Mcl-1 ubiquitination and reduction. Taken together, our data indicate that enhancement of ubiquitination-dependent Mcl-1 turnover might be a promising approach for cancer treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

Gao

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

show abstract

“…However, it remains unclear what apoptotic stimuli trigger Mcl-1S upregulation. Moreover, while many other pro-apoptotic proteins are known to antagonize survival functions of Mcl-1 (Senichkin et al, 2019), the pro-death role of Mcl-1S seems to be redundant in the cell. Arguably, the cell could also exploit Mcl-1S for other processes, and the highly selective interaction between Mcl-1S and Mcl-1L might lie beyond apoptotic regulation.…”

Section: Discussionmentioning

confidence: 99%

“…It is noteworthy that even high concentrations of the compound did not cause apoptosis in the studied cell line (Supplementary Figure 5). It is known that S63845 binding results in the stabilization of Mcl-1L, which is why the accumulation of Mcl-1L serves as an indicator of the inhibitory action of S63845 (Senichkin et al, 2019). Accordingly, 300 nM concentration of S63845 was used in the cell cycle-related experiments, as this dose allowed to obtain the highest accumulation of Mcl-1L (300 nM, Supplementary Figure 5).…”

Section: Mcl-1s Overexpression or Mcl-1l Knockdown Causes A Faster Prmentioning

confidence: 99%

“…MCL1 is known to give rise to at least two alternative splicing (AS) isoforms -antiapoptotic Mcl-1L (traditionally abbreviated as Mcl-1) and proapoptotic Mcl-1S. Mcl-1L protein contains BH1-BH4 motifs, three of which form a BH3-binding groove for sequestration of proapoptotic proteins, whereas only BH3 and BH4 motifs are found in Mcl-1S, thus establishing its proapoptotic characteristics (Senichkin et al, 2019). Moreover, it was shown that Mcl-1L is the only Bcl-2 family protein that binds to Mcl-1S (Bae et al, 2000;Stewart et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Upregulation of Mcl-1S Causes Cell-Cycle Perturbations and DNA Damage Accumulation

Streletskaia

Senichkin

Prikazchikova

et al. 2020

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

As an important regulator of apoptosis, Mcl-1 protein, a member of the Bcl-2 family, represents an attractive target for cancer treatment. The recent development of novel small molecule compounds has allowed Mcl-1-inhibitory therapy to proceed to clinical trials in cancer treatment. However, the possible adverse effects of either direct inhibition of Mcl-1 or upregulation of Mcl-1S, proapoptotic isoform resulting from alternative splicing of Mcl-1, remain unclear. Here, we investigated changes in Mcl-1S levels during cell cycle and the cell cycle-related functions of Mcl-1 isoforms to address the above-mentioned concerns. It was shown that an anti-mitotic agent monastrol caused accumulation of Mcl-1S mRNA, although without increasing the protein level. In contrast, both mRNA and protein levels of Mcl-1S accrued during the premitotic stages of the normal cell cycle progression. Importantly, Mcl-1S was observed in the nuclear compartment and an overexpression of Mcl-1S, as well as knockdown of Mcl-1, accelerated the progression of cells into mitosis and resulted in DNA damage accumulation. Surprisingly, a small molecule inhibitor of Mcl-1, BH3-mimetic S63845, did not affect the cell cycle progression or the amount of DNA damage. In general, upregulated Mcl-1S protein or genetically inhibited Mcl-1L were associated with the cell cycle perturbations and DNA damage accumulation in normal and cancer cells. At the same time, BH3-mimetic to Mcl-1 did not affect the cell cycle progression, suggesting that direct inhibition of Mcl-1 is devoid of cell-cycle related undesired effects.

show abstract

“…Apoptosis, known as programmed cell death, suppresses carcinogenesis in normal cells due to various genes [20]. As an anti-apoptotic protein, Mcl-1 belongs to the BCL-2 family, which is closely connected to inhibitions of mitochondrial apoptosis [21]. Blocking Mcl-1 makes tumour cells more susceptible to anticancer agents [22].…”

Section: Discussionmentioning

confidence: 99%

Lithium Chloride Induces Apoptosis in Human Choroidal Melanoma Cells via the NOXA/Mcl-1 Axis and Induction of ER Stress

Zhang¹,

Zhang²,

Li³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Choroidal melanoma is the most common primary intraocular malignancy that occurs in adults. Lithium chloride (LiCl) has been safely used in the clinic to treat psychiatric disorders for several decades. In this study, we aimed to understand whether LiCl exerts anticancer effects on choroidal melanoma cells and elucidate the underlying molecular mechanisms. Methods: Human choroidal melanoma cells were treated with LiCl, and cell survival was assessed with MTT assays. Cell proliferation was measured by plate colony formation assays. Cell apoptosis was evaluated using flow cytometry, and proteins were detected using western blotting. A human choroidal melanoma xenograft model was established to demonstrate the effect of LiCl on human choroidal melanoma in vivo. An unpaired t-test was used to compare differences between two groups, and one-way ANOVA was used to compare differences among more than two groups.Results: We found that LiCl inhibited cell survival and clonogenic potential and induced apoptosis in human choroidal melanoma cells. LiCl also reduced the proliferation of choroidal melanoma cells in vivo. Moreover, the upregulation of NOXA and downregulation of Mcl-1 were responsible for LiCl-induced apoptosis. Mcl-1 overexpression obviously impaired LiCl-induced apoptosis and cleavage of casp8, casp9, casp3 and PARP. Moreover, the protein expression of endoplasmic reticulum stress markers, including IRE1α, Bip, p-eIF2α, ATF4 and CHOP, was upregulated following treatment with LiCl. Conclusions: In summary, LiCl induced an endoplasmic reticulum stress response while activating intrinsic apoptosis. Furthermore, the NOXA/Mcl-1 axis contributed to LiCl-induced apoptosis both in vitro and in vivo. The present study provides important mechanistic insight into potential cancer treatments involving LiCl and enhances the understanding of human choroidal melanoma.

show abstract

Molecular Comprehension of Mcl-1: From Gene Structure to Cancer Therapy

Cited by 77 publications

References 103 publications

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

Upregulation of Mcl-1S Causes Cell-Cycle Perturbations and DNA Damage Accumulation

Lithium Chloride Induces Apoptosis in Human Choroidal Melanoma Cells via the NOXA/Mcl-1 Axis and Induction of ER Stress

Contact Info

Product

Resources

About