Targeting Vesicle Trafficking: An Important Approach to Cancer Chemotherapy

Wright, Peter V.

doi:10.2174/157489208784638730

Cited by 41 publications

(25 citation statements)

References 70 publications

(133 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, c-Abl also activates cathepsins by promoting endosome maturation, which is important since abnormal vesicular trafficking plays a key role in cancer progression (38). The effects of silencing/inhibiting c-Abl on endosome distribution are reminiscent of the effects observed following overexpression of wild-type Rab5 or dominant-negative Rab7, indicating that depletion of c-Abl may prevent Rab5/Rab7 switching (32, 39).…”

Section: Discussionmentioning

confidence: 99%

c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer

et al. 2013

View full text Add to dashboard Cite

Metastasis suppressors comprise a growing class of genes whose downregulation triggers metastatic progression. In contrast to tumor suppressors, metastasis suppressors are rarely mutated or deleted, and little is known regarding the mechanisms by which their expression is downregulated. Here, we demonstrate that the metastasis suppressor, NM23-H1, is degraded by lysosomal cysteine cathepsins (L,B), which directly cleave NM23-H1. In addition, activation of c-Abl and Arg oncoproteins induces NM23-H1 degradation in invasive cancer cells by increasing cysteine cathepsin transcription and activation. Moreover, c-Abl activates cathepsins by promoting endosome maturation, which facilitates trafficking of NM23-H1 to the lysosome where it is degraded. Importantly, the invasion- and metastasis-promoting activity of c-Abl/Arg is dependent on their ability to induce NM23-H1 degradation, and the pathway is clinically relevant as c-Abl/Arg activity and NM23-H1 expression are inversely correlated in primary breast cancers and melanomas. Thus, we demonstrate a novel mechanism by which cathepsin expression is upregulated in cancer cells (via Abl kinases). We also identify a novel role for intracellular cathepsins in invasion and metastasis (degradation of a metastasis suppressor). Finally, we identify novel crosstalk between oncogenic and metastasis suppressor pathways, thereby providing mechanistic insight into the process of NM23-H1 loss, which may pave the way for new strategies to restore NM23-H1 expression and block metastatic progression.

show abstract

Section: Discussionmentioning

confidence: 99%

c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Rab proteins function as mediators of the complex events involved in the accurate docking and fusion of transport vesicles with their targets (9). Numerous studies have demonstrated that vesicle trafficking and exocytosis have significant roles in tumorigenesis (10). Rab27B is a member of a subfamily of Rabs.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Rab27B is correlated with distant metastasis and poor prognosis in ovarian cancer

et al. 2016

View full text Add to dashboard Cite

Abstract. The secretory small guanosine-5'-triphosphate-binding enzyme, Rab27B, has been identified to be an oncogene that is involved in the progression of certain tumors. The current study was designed to evaluate the expression pattern of Rab27B in ovarian cancer (OC), borderline tumors and benign ovarian adenoid tumors, as well as its association with survival prognosis and clinical parameters. The expression of Rab27B protein was examined by immunohistochemistry in 204 patients who had undergone ovarian resection without preoperative systemic chemotherapy at the Surgical Department of the Affiliated Hospital of Nantong University (Nantong, China), including 57 benign ovarian adenoid tumors, 44 borderline tumors and 103 malignant tumors. Rab27B expression and clinicopathological features were analyzed with the χ 2 test. Patient survival rate was analyzed with the Kaplan-Meier method. Univariate and multivariate analysis of the prognostic factors was performed using the Cox regression model. Increased expression of Rab27B was positively correlated with histological type (P=0.012), level of differentiation (P=0.015), lymph node metastasis (P=0.024), distant metastasis (P<0.001) and International Federation of Gynecology and Obstetrics stage (P=0.001). Survival analysis revealed an association between Rab27B-positivity and poor overall survival rate. Multivariate analysis indicated that Rab27B (P<0.031) and distant metastases (P=0.031) were independent prognostic factors for OC patients' survival. The results of the present study supported the hypothesis that Rab27B may be a valuable prognostic indicator in patients with OC.

show abstract

“…Some immunotoxin-based anti-cancer drugs enter cells by receptor mediated endocytosis to kill tumour cells11. Vesicle trafficking, including the release of extracellular micro-vesicles, is critical in carcinogenesis, which involves invasion, metastasis, cell cycle regulation, angiogenesis, tumour immune privilege, neoplastic coagulopathy and multidrug resistance (MDR)12. Moreover, one study in eukaryotic cells pointed out that the balance between exocytosis and endocytosis is critical for generating the membrane domains recognized by sterol-targeting antibiotics, determining their efficacy13.…”

mentioning

confidence: 99%

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Kadioglu

Cao

Kosyakova

et al. 2016

Sci Rep

View full text Add to dashboard Cite

We systematically characterised multifactorial multidrug resistance (MDR) in CEM/ADR5000 cells, a doxorubicin-resistant sub-line derived from drug-sensitive, parental CCRF-CEM cells developed in vitro. RNA sequencing and network analyses (Ingenuity Pathway Analysis) were performed. Chromosomal aberrations were identified by array-comparative genomic hybridisation (aCGH) and multicolour fluorescence in situ hybridisation (mFISH). Fifteen ATP-binding cassette transporters and numerous new genes were overexpressed in CEM/ADR5000 cells. The basic karyotype in CCRF-CEM cells consisted of 47, XX, der(5)t(5;14) (q35.33;q32.3), del(9) (p14.1), +20. CEM/ADR5000 cells acquired additional aberrations, including X-chromosome loss, 4q and 14q deletion, chromosome 7 inversion, balanced and unbalanced two and three way translocations: t(3;10), der(3)t(3;13), der(5)t(18;5;14), t(10;16), der(18)t(7;18), der(18)t(21;18;5), der(21;21;18;5) and der(22)t(9;22). CCRF-CEM consisted of two and CEM/ADR5000 of five major sub-clones, indicating genetic tumor heterogeneity. Loss of 3q27.1 in CEM/ADR5000 caused down-regulation of ABCC5 and ABCF3 expression, Xq28 loss down-regulated ABCD1 expression. ABCB1, the most well-known MDR gene, was 448-fold up-regulated due to 7q21.12 amplification. In addition to well-known drug resistance genes, numerous novel genes and genomic aberrations were identified. Transcriptomics and genetics in CEM/AD5000 cells unravelled a range of MDR mechanisms, which is much more complex than estimated thus far. This may have important implications for future treatment strategies.

show abstract

Targeting Vesicle Trafficking: An Important Approach to Cancer Chemotherapy

Cited by 41 publications

References 70 publications

c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer

c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer

Overexpression of Rab27B is correlated with distant metastasis and poor prognosis in ovarian cancer

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

Contact Info

Product

Resources

About