Myc Regulation of a Mitochondrial Trafficking Network Mediates Tumor Cell Invasion and Metastasis

Agarwal, Ekta; Altman, Brian J.; Seo, Jae Ho; Bertolini, Irene; Ghosh, Jagadish C.; Kaur, Amanpreet; Kossenkov, Andrew V.; Languino, Lucia R.; Gabrilovich, Dmitry I.; Speicher, David W.; Dang, Chi V.; Altieri, Dario C.

doi:10.1128/mcb.00109-19

Cited by 29 publications

(31 citation statements)

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“…The role of oncogenic Myc [35] in this pathway, which may be responsible for the overexpression of MFF in primary and metastatic tumours, in vivo, fits well with an expanding role of Myc in mitochondrial reprogramming in cancer. In addition to oxidative phosphorylation gene expression [36] and modulation of multiple bioenergetics pathways [37], Myc-directed transcription has been associated with mitochondrial dynamics, promoting changes in organelle structure that favour therapy resistance [38] or heightened subcellular mitochondrial trafficking to fuel tumour cell invasion and metastasis [29].…”

Section: Discussionmentioning

confidence: 99%

“…Benign prostatic hyperplasia (BPH-1) cells were a gift from Dr. Simon Hayward (Vanderbilt University, Nashville, TN) and primary human foreskin fibroblasts (HFF) were a gift from Dr. Meenhard Herlyn (The Wistar Institute, Philadelphia, PA). Neuroblastoma SHEP21N, SHEP21-NMycER cells containing a conditionally-regulated N-Myc transgene were as described [30] and used in recent studies of mitochondrial reprogramming in cancer [29]. In these cells, treatment with 50 ng/ml doxycycline (Dox) for 48 h suppresses N-Myc expression, whereas addition of 4-hydroxytamoxifen (4OHT, 0.5 μg/ml) results in strong N-Myc induction.…”

Section: Methodsmentioning

confidence: 99%

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Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer

et al. 2019

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BackgroundMitochondrial functions are exploited in cancer and provide a validated therapeutic target. However, how this process is regulated has remained mostly elusive and the identification of new pathways that control mitochondrial integrity in cancer is an urgent priority.MethodsWe studied clinically-annotated patient series of primary and metastatic prostate cancer, representative cases of multiple myeloma (MM) and publicly available genetic databases. Gene regulation studies involved chromatin immunoprecipitation, PCR amplification and Western blotting of conditional Myc-expressing cell lines. Transient or stable gene silencing was used to quantify mitochondrial functions in bioenergetics, outer membrane permeability, Ca2+ homeostasis, redox balance and cell death. Tumorigenicity was assessed by cell proliferation, colony formation and xenograft tumour growth.FindingsWe identified Mitochondrial Fission Factor (MFF) as a novel transcriptional target of oncogenic Myc overexpressed in primary and metastatic cancer, compared to normal tissues. Biochemically, MFF isoforms, MFF1 and MFF2 associate with the Voltage-Dependent Anion Channel-1 (VDAC1) at the mitochondrial outer membrane, in vivo. Disruption of this complex by MFF silencing induces general collapse of mitochondrial functions with increased outer membrane permeability, loss of inner membrane potential, Ca2+ unbalance, bioenergetics defects and activation of cell death pathways. In turn, this inhibits tumour cell proliferation, suppresses colony formation and reduces xenograft tumour growth in mice.InterpretationAn MFF-VDAC1 complex is a novel regulator of mitochondrial integrity and actionable therapeutic target in cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer

et al. 2019

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“…Mitochondrial dynamics was shown to be reprogrammed in tumor cells via gathering mitochondria at the cortical cytoskeleton (Caino et al, 2016). The mechanism could power the membrane machinery of cell movements, maintained phosphorylation of cell motility kinases, and heightened tumor invasion, chemotaxis, and metastasis (Caino et al, 2016; Agarwal et al, 2019). Besides, remodeling of mitochondrial functions is considered the commonest modified downstream of MYC gene, due to the MYC-dependent transcriptional control of GTPase RHOT1/RHOT2 and posttranslational modifications, such as RHOT phosphorylation by PINK kinase (Wang et al, 2011; Bailey et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Identification of Prognostic and Metastatic Alternative Splicing Signatures in Kidney Renal Clear Cell Carcinoma

Meng

Huang

Zeng

et al. 2019

Front. Bioeng. Biotechnol.

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Background: Kidney renal clear cell carcinoma (KIRC) is the malignancy originated from the renal epithelium, with a high rate of distant metastasis. Aberrant alternative splicing (AS) of pre-mRNA are widely reported to be involved in the tumorigenesis and metastasis of multiple cancers. The aim of this study is to explore the mechanism of alternative splicing events (ASEs) underlying tumorigenesis and metastasis of KIRC.Methods: RNA-seq of 537 KIRC samples downloaded from the TCGA database and ASEs data from the TCGASpliceSeq database were used to identify ASEs in patients with KIRC. The univariate and Lasso regression analysis were used to screen the most significant overall survival-related ASEs (OS-SEs). Based on those, the OS-SEs model was proposed. The interaction network of OS-SEs and splicing factors (SFs) with absolute value of correlation coefficient value >0.750 was constructed by Pearson correlation analysis. The OS-SEs significantly related to distant metastasis and clinical stage were identified by non-parametric test, and those were also integrated into co-expression analysis with prognosis-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways identified by Gene Set Variation Analysis (GSVA). ASEs with significance were selected for multiple online database validation.Results: A total of prognostic 6,081 overall survival-related ASEs (OS-SEs) were identified by univariate Cox regression analysis and a prediction model was constructed based on 5 OS-SEs screened by Lasso regression with the Area Under Curve of 0.788. Its risk score was also illustrated to be an independent predictor, which the good reliability of the model. Among 390 identified candidate SFs, DExD-Box Helicase 39B (DDX39B) was significantly correlated with OS and metastasis. After external database validation, Retained Intron of Ras Homolog Family Member T2 (RHOT2) and T-Cell Immune Regulator 1 (TCIRG1) were identified. In the co-expression analysis, overlapped co-expression signal pathways for RHOT2 and TCIRG1 were sphingolipid metabolism and N-glycan biosynthesis.Conclusions: Based on the results of comprehensive bioinformatic analysis, we proposed that aberrant DDX39B regulated RHOT2-32938-RI and TCIRG1-17288-RI might be associated with the tumorigenesis, metastasis, and poor prognosis of KIRC via sphingolipid metabolism or N-glycan biosynthesis pathway.

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“…Tumour metastasis, a process implicated in 90% of cancer deaths, is also dictated by changes in mitochondrial function and distribution [104]. Agarwal et al [105] demonstrated that the exploitation of mitochondrial trafficking is a key hallmark of myc-driven tumour progression, where subcellular mitochondrial trafficking to the cortical cytoskeleton is vital for tumour cell invasion and metastasis. Myc proteins are products of oncogenes, often amplified in human cancers, which promote tumour growth and progression.…”

Section: Mitochondrial Targeting To Treat Cancermentioning

confidence: 99%

“…Myc proteins are products of oncogenes, often amplified in human cancers, which promote tumour growth and progression. They have been associated with the control of the gene network of mitochondrial trafficking and changes in the expression of OXPHOS genes and bioenergetics pathways [105]. Mitochondrial trafficking and redistribution is a vital and standard process in healthy neurones, where mitochondria are repositioned to axon terminals to fuel highly energy-intensive processes such as synaptic functions and active growth cones [106]; however, the same protein network is exploited by tumour cells to propel metastasis [107].…”

Section: Mitochondrial Targeting To Treat Cancermentioning

confidence: 99%

Impact of pharmacological agents on mitochondrial function: a growing opportunity?

Stoker

Newport

Hulit³

et al. 2019

Biochemical Society Transactions

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Present-day drug therapies provide clear beneficial effects as many diseases can be driven into remission and the symptoms of others can be efficiently managed; however, the success of many drugs is limited due to both patient non-compliance and adverse off-target or toxicity-induced effects. There is emerging evidence that many of these side effects are caused by drug-induced impairment of mitochondrial function and eventual mitochondrial dysfunction. It is imperative to understand how and why drug-induced side effects occur and how mitochondrial function is affected. In an aging population, age-associated drug toxicity is another key area of focus as the majority of patients on medication are older. Therefore, with an aging population possessing subtle or even more dramatic individual differences in mitochondrial function, there is a growing necessity to identify and understand early on potentially significant drug-associated off-target effects and toxicity issues. This will not only reduce the number of unwanted side effects linked to mitochondrial toxicity but also identify useful mitochondrial-modulating agents. Mechanistically, many successful drug classes including diabetic treatments, antibiotics, chemotherapies and antiviral agents have been linked to mitochondrial targeted effects. This is a growing area, with research to repurpose current medications affecting mitochondrial function being assessed in cancer, the immune system and neurodegenerative disorders including Parkinson's disease. Here, we review the effects that pharmacological agents have on mitochondrial function and explore the opportunities from these effects as potential disease treatments. Our focus will be on cancer treatment and immune modulation.

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Myc Regulation of a Mitochondrial Trafficking Network Mediates Tumor Cell Invasion and Metastasis

Cited by 29 publications

References 65 publications

Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer

Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer

Identification of Prognostic and Metastatic Alternative Splicing Signatures in Kidney Renal Clear Cell Carcinoma

Impact of pharmacological agents on mitochondrial function: a growing opportunity?

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