Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy

Guo, Chen; Magis, Andrew T.; Xu, Ke; Park, Dongkyoo; Yu, David S.; Owonikoko, Taofeek K.; Sica, Gabriel L.; Satola, Sarah W.; Ramalingam, Suresh S.; Curran, Walter J.; Doetsch, Paul W.; Deng, Xingming

doi:10.1172/jci92742

Cited by 51 publications

(49 citation statements)

References 64 publications

(79 reference statements)

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“…MCL‐1 is a unique anti‐apoptotic BCL‐2 family member that is overexpressed in many tumour types . For example, Chen G et al reported that targeting MCL‐1 enhanced the sensitivity of DNA replication stress to cancer treatment . In addition, Zhan Z et al also reported that MCL‐1 can increase the anti‐apoptotic ability of GC cells, thereby promoting the proliferation of GC cells .…”

Section: Discussionmentioning

confidence: 99%

Long non‐coding RNA MYOSLID functions as a competing endogenous RNA to regulate MCL‐1 expression by sponging miR‐29c‐3p in gastric cancer

Han

Jiang

et al. 2019

Cell Proliferation

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Objective Long non‐coding RNA (lncRNA) has become an important regulator of many human malignancies. However, the biological role and clinical significance of most lncRNA in gastric cancer (GC) remain unclear. Methods We investigate the biological function, mechanism of action and clinical expression of lncRNA MYOSLID in GC. First, we analysed the differential expression of lncRNA MYOSLID in GC tissues and non‐cancerous tissues by analysing the sequencing data obtained from The Cancer Genome Atlas. Subsequently, we verified that lncRNA MYOSLID regulates the proliferation and apoptosis of GC cells by acting as a ceRNA against miR‐29c‐3p. The nude mouse xenograft was used to further confirm the functional significance of lncRNA MYOSLID in vivo. Results We found for the first time that the expression of lncRNA MYOSLID was significantly up‐regulated in GC tissues, and the up‐regulation of lncRNA MYOSLID in GC was correlated with tumour size, AJCC stage, depth of invasion and survival time. In addition, apoptosis and growth arrest can be induced in vitro after knockdown of lncRNA MYOSLID, which inhibits tumorigenesis in mouse xenografts in vivo. Further in‐depth studies revealed that lncRNA MYOSLID acts as a ceRNA of miR‐29c‐3p, resulting in de‐repression of its downstream target gene MCL‐1. Conclusion The lncRNA MYOSLID‐miR‐29c‐3p‐MCL‐1 axis plays a key role in the development of GC. Our findings may provide potential new targets for the diagnosis and treatment of human GC.

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Section: Discussionmentioning

confidence: 99%

Long non‐coding RNA MYOSLID functions as a competing endogenous RNA to regulate MCL‐1 expression by sponging miR‐29c‐3p in gastric cancer

Han

Jiang

et al. 2019

Cell Proliferation

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“…As an Inhibitor of DNA synthesis (Schvartzman et al , 1984), thymidine can arrest cell at G1/S boundary. Here, we describe a detail method to synchronize cells at G1/S boundary by thymidine (Chen et al ., 2018). …”

Section: [Background]mentioning

confidence: 99%

Cell Synchronization by Double Thymidine Block

2018

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Cell synchronization is widely used in studying mechanisms involves in regulation of cell cycle progression. Through synchronization, cells at distinct cell cycle stage could be obtained. Thymidine is a DNA synthesis inhibitor that can arrest cell at G1/S boundary, prior to DNA replication. Here, we present the protocol to synchronize cells at G1/S boundary by using double thymidine block. After release into normal medium, cell population at distinct cell cycle phase could be collected at different time points.

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“…MCL-1 is a unique member of Bcl-2 family that is different from other family members (i.e., Bcl-2, Bcl-xL, Bcl-w and Bfl-1A1), as it holds a considerably long N-terminus [27]. MCL-1 has been shown to be widely expressed in many types of cells, including endothelial cells in a wide range of tissues, such as prostate, breast, endometrium, epidermis, stomach, etc.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Pro-Angiogenic Role of LncRNA HULC in Microvascular Endothelial Cells via Sequestrating miR-124

Yin

et al. 2018

Cell Physiol Biochem

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Background/Aims: HULC is a multifunctional lncRNA that has pro-angiogenic function in various cancers. The present study was designed to see the role of lncRNA HULC in normal endothelial cells angiogenesis. Methods: Cell viability, apoptosis, migration, tube formation and expression levels of angiogenesis-related proteins were respectively assessed in human microvascular endothelial HMEC-1 cells after lncRNA HULC was silenced by shRNA transfection. Cross-regulation between lncRNA HULC and miR-124, and between miR-124 and MCL-1 were detected by qRT-PCR, sequence analysis, and luciferase reporter assay. Results: Silence of lncRNA HULC significantly reduced viability, migration, tube formation and protein levels of VEGF, VEGFR2, CD144 and eNOS in HMEC-1 cells. Meanwhile, silence of lncRNA HULC induced apoptosis in HMEC-1 cells, as Bcl-2 was down-regulated, Bax was up-regulated, and caspase-3 and -9 were cleaved. miR-124 expression was negatively regulated by lncRNA HULC, and HULC worked as a molecular sponge for miR-124, in having miR-124 exhausted. Besides, MCL-1 was a target gene of miR-124. Rescue assay results showed that the effects of lncRNA HULC silence on HMEC-1 cells growth, migration and angiogenesis were abolished by miR-124 suppression. Similarly, the effects of miR-124 on HMEC-1 cells were abolished by MCL-1 overexpression. Furthermore, MCL-1 activated PI3K/AKT and JAK/STAT signaling pathways. Conclusion: These findings suggest a pro-angiogenic role of lncRNA HULC in endothelial cells. The pro-angiogenic actions of lncRNA HULC may be through sponging miR-124, preventing MCL-1 from degradation by miR-124.

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Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy

Cited by 51 publications

References 64 publications

Long non‐coding RNA MYOSLID functions as a competing endogenous RNA to regulate MCL‐1 expression by sponging miR‐29c‐3p in gastric cancer

Long non‐coding RNA MYOSLID functions as a competing endogenous RNA to regulate MCL‐1 expression by sponging miR‐29c‐3p in gastric cancer

Cell Synchronization by Double Thymidine Block

Pro-Angiogenic Role of LncRNA HULC in Microvascular Endothelial Cells via Sequestrating miR-124

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