Global Gene Expression Analysis Reveals a Link between NDRG1 and Vesicle Transport

Askautrud, Hanne A.; Gjernes, Elisabet; Gunnes, Gjermund; Sletten, Marit; Ross, Douglas T.; Børresen-Dale, Anne Lise; Iversen, Nina; Tranulis, Michael A.; Frengen, Eirik

doi:10.1371/journal.pone.0087268

Cited by 30 publications

(24 citation statements)

References 50 publications

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“…Although the clinical status of NDRG1 is well documented, mechanisms by which NDRG1 prevents metastasis remain poorly understood. We and others have shown that NDRG1 may function as a vesicular transport protein (Askautrud et al ., ; Kachhap et al ., ; Pietiainen et al ., ). In the present study, we provide molecular insights into the mechanism by which NDRG1 prevents prostate metastasis.…”

Section: Discussionmentioning

confidence: 99%

The prostate metastasis suppressor gene NDRG1 differentially regulates cell motility and invasion

et al. 2017

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Experimental and clinical evidence suggests that N‐myc downregulated gene 1 (NDRG1) functions as a suppressor of prostate cancer metastasis. Elucidating pathways that drive survival and invasiveness of NDRG1‐deficient prostate cancer cells can help in designing therapeutics to target metastatic prostate cancer cells. However, the molecular mechanisms that lead NDRG1‐deficient prostate cancer cells to increased invasiveness remain largely unknown. In this study, we demonstrate that NDRG1‐deficient prostate tumors have decreased integrin expression and reduced cell adhesion and motility. Our data indicate that loss of NDRG1 differentially affects Rho GTPases. Specifically, there is a downregulation of active RhoA and Rac1 GTPases with a concomitant upregulation of active Cdc42 in NDRG1‐deficient cells. Live cell imaging using a fluorescent sensor that binds to polymerized actin revealed that NDRG1‐deficient cells have restricted actin dynamics, thereby affecting cell migration. These cellular and molecular characteristics are in sharp contrast to what is expected after loss of a metastasis suppressor. We further demonstrate that NDRG1‐deficient cells have increased resistance to anoikis and increased invasiveness which is independent of its elevated Cdc42 activity. Furthermore, NDRG1 regulates expression and glycosylation of EMMPRIN, a master regulator of matrix metalloproteases. NDRG1 deficiency leads to an increase in EMMPRIN expression with a concomitant increase in matrix metalloproteases and thus invadopodial activity. Using a three‐dimensional invasion assay and an in vivo metastasis assay for human prostate xenografts, we demonstrate that NDRG1‐deficient prostate cancer cells exhibit a collective invasion phenotype and are highly invasive. Thus, our findings provide novel insights suggesting that loss of NDRG1 leads to a decrease in actin‐mediated cellular motility but an increase in cellular invasion, resulting in increased tumor dissemination which positively impacts metastatic outcome.

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Section: Discussionmentioning

confidence: 99%

The prostate metastasis suppressor gene NDRG1 differentially regulates cell motility and invasion

et al. 2017

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“…Apart from its role in stress signaling, it also plays a role in vesicular trafficking. 69 V-type proton ATPase subunit E 1 (ATP6V1EJ) is a subunit of the peripheral V1 complex of vacuolar ATPase essential for assembly or catalytic function. A decreased level of a2 vacuolar ATPase, a member of the V-type ATPase could be used as a marker for infertility.…”

Section: Discussionmentioning

confidence: 99%

Proteomic signatures of infertile men with clinical varicocele and their validation studies reveal mitochondrial dysfunction leading to infertility

et al. 2016

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To study the major differences in the distribution of spermatozoa proteins in infertile men with varicocele by comparative proteomics and validation of their level of expression. The study-specific estimates for each varicocele outcome were combined to identify the proteins involved in varicocele-associated infertility in men irrespective of stage and laterality of their clinical varicocele. Expression levels of 5 key proteins (PKAR1A, AK7, CCT6B, HSPA2, and ODF2) involved in stress response and sperm function including molecular chaperones were validated by Western blotting. Ninety-nine proteins were differentially expressed in the varicocele group. Over 87% of the DEP involved in major energy metabolism and key sperm functions were underexpressed in the varicocele group. Key protein functions affected in the varicocele group were spermatogenesis, sperm motility, and mitochondrial dysfunction, which were further validated by Western blotting, corroborating the proteomics analysis. Varicocele is essentially a state of energy deprivation, hypoxia, and hyperthermia due to impaired blood supply, which is corroborated by down-regulation of lipid metabolism, mitochondrial electron transport chain, and Krebs cycle enzymes. To corroborate the proteomic analysis, expression of the 5 identified proteins of interest was validated by Western blotting. This study contributes toward establishing a biomarker “fingerprint” to assess sperm quality on the basis of molecular parameters.

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“…However, the most important phenotype exhibited by NDRG1 nulls is demyelinating neuropathy (Okuda et al., ). Recent studies have demonstrated that NDRG1 is connected to intracellular vesicle transport (Askautrud et al., ). It functions as a Rab4a effector localized to the endosomes and is involved in the trafficking of low‐density lipoprotein receptor (LDLR) (Kachhap et al., ).…”

Section: Introductionmentioning

confidence: 99%

Identification and functional characterization of two missense mutations in NDRG1 associated with Charcot‐Marie‐Tooth disease type 4D

Liu

et al. 2017

Human Mutation

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Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal-recessive demyelinating form of CMT characterized by a severe distal motor and sensory neuropathy. NDRG1 is the causative gene for CMT4D. To date, only four mutations in NDRG1 -c.442C>T (p.Arg148*), c.739delC (p.His247Thrfs*74), c.538-1G>A, and duplication of exons 6-8-have been described in CMT4D patients. Here, using targeted next-generation sequencing examination, we identified for the first time two homozygous missense variants in NDRG1, c.437T>C (p.Leu146Pro) and c.701G>A (p.Arg234Gln), in two Chinese CMT families with consanguineous histories. Further functional studies were performed to characterize the biological effects of these variants. Cell culture transfection studies showed that mutant NDRG1 carrying p.Leu146Pro, p.Arg148*, or p.Arg234Gln variant degraded faster than wild-type NDRG1, resulting in lower protein levels. Live cell confocal microscopy and coimmunoprecipitation analysis indicated that these variants did not disrupt the interaction between NDRG1 and Rab4a protein. However, NDRG1-knockdown cells expressing mutant NDRG1 displayed enlarged Rab4a-positive compartments. Moreover, mutant NDRG1 could not enhance the uptake of DiI-LDL or increase the fraction of low-density lipoprotein receptor on the cell surface. Taken together, our study described two missense mutations in NDRG1 and emphasized the important role of NDRG1 in intracellular protein trafficking.

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Global Gene Expression Analysis Reveals a Link between NDRG1 and Vesicle Transport

Cited by 30 publications

References 50 publications

The prostate metastasis suppressor gene NDRG1 differentially regulates cell motility and invasion

The prostate metastasis suppressor gene NDRG1 differentially regulates cell motility and invasion

Proteomic signatures of infertile men with clinical varicocele and their validation studies reveal mitochondrial dysfunction leading to infertility

Identification and functional characterization of two missense mutations in NDRG1 associated with Charcot‐Marie‐Tooth disease type 4D

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