Expression of TMBIM6 in Cancers: The Involvement of Sp1 and PKC

Junjappa, Raghu Patil; Kim, Hyun-Kyoung; Park, Seong Yeol; Bhattarai, Kashi Raj; Kim, Kyung-Woon; Soh, Jae-Won; Kim, Hyung‐Ryong; Chae, Han-Jung

doi:10.3390/cancers11070974

Cited by 9 publications

(9 citation statements)

References 87 publications

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“…TMBIM6 is a Ca 2+ channel-like protein that lowers the steady-state [Ca 2+ ] ER, which is expressed in the endoplasmic reticulum (ER) membrane surface 1 . It is up-regulated in many cancer types including breast, lung, prostate, nasopharyngeal, and liver cancer 4 – 8 . In our previous study, the overexpression of TMBIM6 promoted cancer metastasis by regulating cell mobility and invasiveness and glucose metabolism 9 .…”

Section: Introductionmentioning

confidence: 99%

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TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation

et al. 2020

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Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, a Ca 2+ channel-like protein, is highly up-regulated in several cancer types. Here, we show that TMBIM6 is closely associated with survival in patients with cervical, breast, lung, and prostate cancer. TMBIM6 deletion or knockdown suppresses primary tumor growth. Further, mTORC2 activation is up-regulated by TMBIM6 and stimulates glycolysis, protein synthesis, and the expression of lipid synthesis genes and glycosylated proteins. Moreover, ER-leaky Ca 2+ from TMBIM6, a unique characteristic, is shown to affect mTORC2 assembly and its association with ribosomes. In addition, we identify that the BIA compound, a poten-tialTMBIM6 antagonist, prevents TMBIM6 binding to mTORC2, decreases mTORC2 activity, and also regulates TMBIM6-leaky Ca 2+ , further suppressing tumor formation and progression in cancer xenograft models. This previously unknown signaling cascade in which mTORC2 activity is enhanced via the interaction with TMBIM6 provides potential therapeutic targets for various malignancies.

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Section: Introductionmentioning

confidence: 99%

“…Suppression of TMBIM6 leads to cell death, which results in reduced tumor development. Recently, we reported that Sp1 and PKC regulate the transcriptional expression of TMBIM6 8 . PKC was also highly expressed in various cancer types, as shown in liver, prostate, and breast cancers 10 , 11 .…”

Section: Introductionmentioning

confidence: 99%

TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation

et al. 2020

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“…TMBIM6, as an important regulatory protein of ER stress, can participate in regulating ER stress signaling pathways. TMBIM6 can directly inhibit IRE1- α activity by binding to its cytoplasmic domain [ 40 ]. This protein is also responsible for controlling calcium release and the ER apoptosis pathway in the ER region [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Quercetin Improves Cardiomyocyte Vulnerability to Hypoxia by Regulating SIRT1/TMBIM6-Related Mitophagy and Endoplasmic Reticulum Stress

Chang

Zhang

Qing

et al. 2021

Oxidative Medicine and Cellular Longevity

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Cardiomyocyte apoptosis is an important pathological mechanism underlying cardiovascular diseases and is commonly caused by hypoxia. Moreover, hypoxic injury occurs not only in common cardiovascular diseases but also following various treatments of heart-related conditions. One of the major mechanisms underlying hypoxic injury is oxidative stress. Quercetin has been shown to exert antioxidant stress and vascular protective effects, making it a promising candidate for treating cardiovascular diseases. Therefore, we examined the protective effect of quercetin on human cardiomyocytes subjected to hypoxia-induced oxidative stress damage and its underlying mechanism. Human cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) in vitro with or without quercetin pretreatment; thereafter, flow cytometry, Cell Counting Kit-8 assay, laser scanning confocal microscopy, quantitative PCR, western blotting, and enzyme-linked immunosorbent assay were performed to analyze the effects of quercetin on cardiomyocytes. We found that H/R induced reactive oxygen species overproduction and endoplasmic reticulum stress, as well as inhibited the function of the mitochondria/endoplasmic reticulum and mitophagy, eventually leading to apoptosis and decreasing the viability of human cardiomyocytes. Quercetin pretreatment inhibited H/R-mediated overproduction of reactive oxygen species and damage caused by oxidative stress, increased mitophagy, regulated mRNA and protein expression of transmembrane BAX inhibitor-1 motif-containing 6 (TMBIM6), regulated endoplasmic reticulum stress, and improved the vulnerability of human cardiomyocytes to H/R. Furthermore, transfection with short interfering RNA against silent information regulator protein 1 (SIRT1) counteracted the protective effects of quercetin on cardiomyocytes. Thus, quercetin was predicted to regulate mitophagy and endoplasmic reticulum stress through SIRT1/TMBIM6 and inhibit H/R-induced oxidative stress damage. These findings may be useful for developing treatments for hypoxic injury-induced cardiovascular diseases and further highlight the potential of quercetin for regulating mitochondrial quality control and endoplasmic reticulum function.

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“…TMBIM6 has been identified as an anti-apoptotic protein due to its protective effect against the pro-apoptotic protein Bax (13). TMBIM6 is upregulated in a number of tumors and is involved in metastasis, whereas the downregulation of TMBIM6 may lead to cancer cell death (14). It has been reported that TMBIM6 is highly expressed in the cells and serum of patients with BC (15).…”

Section: Discussionmentioning

confidence: 99%

miR‑302d‑3p regulates the viability, migration and apoptosis of breast cancer cells through regulating the TMBIM6‑mediated ERK signaling pathway

Liao¹,

Qiu

Bai

2021

Mol Med Rep

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MicroRNAs (miRs/miRNAs) play important roles in the occurrence, metastasis and prognosis of multiple types of cancers. However, the specific role of miR-302d-3p and its underlying mechanism in breast cancer (BC) have not yet been reported. The present study aimed to identify the role of miR-302D-3p in BC and its potential mechanism using BC cell lines MCF7 and MDA-MB-231 and normal breast epithelial cell MCF-10A. Cancer and paracancerous tissue from patients with BC were also used. Reverse transcription-quantitative PCR was performed to detect the expression of miR-302d-3p and transmembrane Bax inhibitor motif containing 6 (TMBIM6). Dual-luciferase reporter assays verified the binding sites of miR-302d-3p and TMBIM6. Immunohistochemistry was used to measure the expression of TMBIM6. Cell transfection techniques were used to overexpress or interfere with miR-302d-3p and TMBIM6. A Cell Counting Kit-8 assay was performed to detect cell viability, and migration was measured using a wound healing assay. Apoptosis was detected by flow cytometry. The expression levels of apoptosis-related proteins and pathway-related proteins were detected by western blotting. The expression of miR-302d-3p in BC cell lines was found to be downregulated. It was also demonstrated that miR-302d-3p could inhibit cell viability and migration and promote apoptosis. The expression of TMBIM6 in BC cell lines and tissues was upregulated. Upregulated miR-302d-3p was shown to inhibit viability and migration, and promote apoptosis by targeting TMBIM6, during which extracellular signal-regulated kinase (ERK) and its phosphorylation were inhibited in the ERK signaling pathway in cells. Overall, the present study demonstrated that miR-302d-3p could regulate the viability, migration and apoptosis of BC cells through regulating TMBIM6-mediated ERK signaling pathway.

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Expression of TMBIM6 in Cancers: The Involvement of Sp1 and PKC

Cited by 9 publications

References 87 publications

TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation

TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation

Quercetin Improves Cardiomyocyte Vulnerability to Hypoxia by Regulating SIRT1/TMBIM6-Related Mitophagy and Endoplasmic Reticulum Stress

miR‑302d‑3p regulates the viability, migration and apoptosis of breast cancer cells through regulating the TMBIM6‑mediated ERK signaling pathway

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