A New Role for the Mitochondrial Pro-apoptotic Protein SMAC/Diablo in Phospholipid Synthesis Associated with Tumorigenesis

Paul, Avijit Kumar; Krelin, Yakov; Arif, Tasleem; Jeger, Rina; Shoshan‐Barmatz, Varda

doi:10.1016/j.ymthe.2017.12.020

Cited by 33 publications

(61 citation statements)

References 54 publications

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“…SMAC/Diablo is overexpressed in several cancer types 70–72 in spite of being a pro‐apoptotic protein 73,74 . This apparent paradox was solved when we identified a new non‐apoptotic function for SMAC/Diablo that is associated with regulating phospholipid synthesis important for cancer cell survival 72 . A tissue array of GBM patient samples stained with SMAC/Diablo‐specific antibodies revealed high levels of SMAC/Diablo in GBM, with the proteins localized to the nucleus (Figure 7b,c).…”

Section: Resultsmentioning

confidence: 99%

Mitochondria and nucleus cross‐talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer

et al. 2020

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The cross‐talk between the mitochondrion and the nucleus regulates cellular functions, including differentiation and adaptation to stress. Mitochondria supply metabolites for epigenetic modifications and other nuclear‐associated activities and certain mitochondrial proteins were found in the nucleus. The voltage‐dependent anion channel 1 (VDAC1), localized at the outer mitochondrial membrane (OMM) is a central protein in controlling energy production, cell growth, Ca2+ homeostasis, and apoptosis. To alter the cross‐talk between the mitochondria and the nucleus, we used specific siRNA to silence the expression of VDAC1 in glioblastoma (GBM) U87‐MG and U118‐MG cell‐derived tumors, and then monitored the nuclear localization of mitochondrial proteins and the methylation and acetylation of histones. Depletion of VDAC1 from tumor cells reduced metabolism, leading to inhibition of tumor growth, and several tumor‐associated processes and signaling pathways linked to cancer development. In addition, we demonstrate that certain mitochondrial pro‐apoptotic proteins such as caspases 3, 8, and 9, and p53 were unexpectedly overexpressed in tumors, suggesting that they possess additional non‐apoptotic functions. VDAC1 depletion and metabolic reprograming altered their expression levels and subcellular localization, specifically their translocation to the nucleus. In addition, VDAC1 depletion also leads to epigenetic modifications of histone acetylation and methylation, suggesting that the interchange between metabolism and cancer signaling pathways involves mitochondria‐nucleus cross‐talk. The mechanisms regulating mitochondrial protein trafficking into and out of the nucleus and the role these proteins play in the nucleus remain to be elucidated.

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Section: Resultsmentioning

confidence: 99%

Mitochondria and nucleus cross‐talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer

et al. 2020

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“…TUNEL staining for the visualisation of apoptotic cells showed no significant apoptosis in si-NT-TTs or si-hVDAC1-TTs derived from U-87MG, A549 or MDA-MB-231 cells (Figure 7A). The expression levels of pro-apoptotic SMAC, shown to possess non-apoptotic functions [45], as well as the anti-apoptotic protein Bcl-xL, were decreased in si-hVDAC1-TTs, while Bax levels were unchanged or increased in the three types of tumours (Figure 7B–G).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial VDAC1 Silencing Leads to Metabolic Rewiring and the Reprogramming of Tumour Cells into Advanced Differentiated States

Arif

Paul

Krelin

et al. 2018

Cancers

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Oncogenic properties, along with the metabolic reprogramming necessary for tumour growth and motility, are acquired by cancer cells. Thus, tumour metabolism is becoming a target for cancer therapy. Here, cancer cell metabolism was tackled by silencing the expression of voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein that controls cell energy, as well as metabolic and survival pathways and that is often over-expressed in many cancers. We demonstrated that silencing VDAC1 expression using human-specific siRNA (si-hVDAC1) inhibited cancer cell growth, both in vitro and in mouse xenograft models of human glioblastoma (U-87MG), lung cancer (A549), and triple negative breast cancer (MDA-MB-231). Importantly, treatment with si-hVDAC1 induced metabolic rewiring of the cancer cells, reversing their oncogenic properties and diverting them towards differentiated-like cells. The si-hVDAC1-treated residual “tumour” showed reprogrammed metabolism, decreased proliferation, inhibited stemness and altered expression of genes and proteins, leading to cell differentiation toward less malignant lineages. These VDAC1 depletion-mediated effects involved alterations in master transcription factors associated with cancer hallmarks, such as highly increased expression of p53 and decreased expression of HIF-1a and c-Myc that regulate signalling pathways (e.g., AMPK, mTOR). High expression of p53 and the pro-apoptotic proteins cytochrome c and caspases without induction of apoptosis points to functions for these proteins in promoting cell differentiation. These results clearly show that VDAC1 depletion similarly leads to a rewiring of cancer cell metabolism in breast and lung cancer and glioblastoma, regardless of origin or mutational status. This metabolic reprogramming results in cell growth arrest and inhibited tumour growth while encouraging cell differentiation, thus generating cells with decreased proliferation capacity. These results further suggest VDAC1 to be an innovative and markedly potent therapeutic target.

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“…This discrepancy between the increased SMAC expression level seen in many cancers and its pro-apoptotic activity [ 37 ] may result from another unidentified function of SMAC. Recently, we demonstrated the essential function of SMAC for cell and tumor growth in lung cancer [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

A molecular signature of lung cancer: potential biomarkers for adenocarcinoma and squamous cell carcinoma

et al. 2017

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Adenocarcinoma (AC) and squamous cell carcinoma (SCC), sub-types of non-small cell lung cancer (NSCLC), both present unique features at the genome, epigenome, transcriptome and proteome levels, as well as shared clinical and histopathological characteristics, but differ in terms of treatment. To ensure proper treatment, one must be able to distinguish between these sub-types. Here, we identify novel biomarker proteins in NSCLC, allowing for distinguishing between the AC and SCC sub-types. Proteomics analysis distinguished between healthy and tumor tissues, with the expression level of 1,494 proteins being altered, 378 of which showed a ≥|100|-fold change. Enrichment of proteins related to protein synthesis and degradation, and of proteins associated with mitochondria, metabolism, and apoptosis, was found. Network analysis defined groups of proteins, such as those associated with cell metabolic processes or with fatty acid/lipid metabolism and transport. Several biomarkers that enable for distinguishing between AC and SCC were identified here for the first time, and together with previous reports confirmed here, led us to propose a list of proteins differentially expressed in SCC and AC. Some of these biomarkers are clear signatures for AC or SCC and four of them are secreted proteins. The presence of the mitochondrial protein SMAC/Diablo in the nucleus was found to be a signature for SCC. Precise diagnosis of AC and SCC is essential for selecting appropriate treatment and thus, increasing patient life expectancy. Finally, the search for drugs that target some of these biomarkers may lead to new treatments for lung cancer.

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A New Role for the Mitochondrial Pro-apoptotic Protein SMAC/Diablo in Phospholipid Synthesis Associated with Tumorigenesis

Cited by 33 publications

References 54 publications

Mitochondria and nucleus cross‐talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer

Mitochondria and nucleus cross‐talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer

Mitochondrial VDAC1 Silencing Leads to Metabolic Rewiring and the Reprogramming of Tumour Cells into Advanced Differentiated States

A molecular signature of lung cancer: potential biomarkers for adenocarcinoma and squamous cell carcinoma

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