Novel functions for Rab GTPases in multiple aspects of tumour progression

Rab GTPases are master regulators of intracellular trafficking and, in recent years, their role in the control of different aspects of tumour progression has emerged. In the present review, we show that Rab GTPases are disregulated in many cancers and have central roles in tumour cell migration, invasion, proliferation, communication with stromal cells and the development of drug resistance. As a consequence, Rab proteins may be novel potential candidates for the development of anticancer drugs and, in this context, the preliminary results obtained with an inhibitor of Rab function are also discussed.

Download Full-text

Structures ofDrosophila melanogasterRab2 and Rab3 bound to GMPPNP

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x1402617x ◽

2015 ◽

Vol 71 (1) ◽

pp. 34-40 ◽

Cited By ~ 4

Author(s):

Jennifer A. Lardong ◽

Jan H. Driller ◽

Harald Depner ◽

Christoph Weise ◽

Astrid Petzoldt ◽

...

Keyword(s):

Conformational Changes ◽

Intracellular Trafficking ◽

Large Family ◽

Cysteine Residue ◽

Effector Proteins ◽

Rab Proteins ◽

Rab Gtpases ◽

Ras Proteins ◽

Transport Vesicles ◽

Switch Regions

Rab GTPases belong to the large family of Ras proteins. They act as key regulators of membrane organization and intracellular trafficking. Functionally, they act as switches. In the active GTP-bound form they can bind to effector proteins to facilitate the delivery of transport vesicles. Upon stimulation, the GTP is hydrolyzed and the Rab proteins undergo conformational changes in their switch regions. This study focuses on Rab2 and Rab3 fromDrosophila melanogaster. Whereas Rab2 is involved in vesicle transport between the Golgi and the endoplasmatic reticulum, Rab3 is a key player in exocytosis, and in the synapse it is involved in the assembly of the presynaptic active zone. Here, high-resolution crystal structures of Rab2 and Rab3 in complex with GMPPNP and Mg2+are presented. In the structure of Rab3 a modified cysteine residue is observed with an enigmatic electron density attached to its thiol function.

Download Full-text

Rab GTPases and microtubule motors

Biochemical Society Transactions ◽

10.1042/bst0391202 ◽

2011 ◽

Vol 39 (5) ◽

pp. 1202-1206 ◽

Cited By ~ 69

Author(s):

Conor P. Horgan ◽

Mary W. McCaffrey

Keyword(s):

Protein Interactions ◽

Intracellular Trafficking ◽

Cytoplasmic Dynein ◽

Small Gtpases ◽

Transport Processes ◽

Effector Proteins ◽

Rab Proteins ◽

Rab Gtpases ◽

Microtubule Motor ◽

Rab Effector

Rab proteins are a family of small GTPases which, since their initial identification in the late 1980s, have emerged as master regulators of all stages of intracellular trafficking processes in eukaryotic cells. Rabs cycle between distinct conformations that are dependent on their guanine-nucleotide-bound status. When active (GTP-bound), Rabs are distributed to the cytosolic face of specific membranous compartments where they recruit downstream effector proteins. Rab–effector complexes then execute precise intracellular trafficking steps, which, in many cases, include vesicle motility. Microtubule-based kinesin and cytoplasmic dynein motor complexes are prominent among the classes of known Rab effector proteins. Additionally, many Rabs associate with microtubule-based motors via effectors that act as adaptor molecules that can simultaneously associate with the GTP-bound Rab and specific motor complexes. Thus, through association with motor complexes, Rab proteins can allow for membrane association and directional movement of various vesicular cargos along the microtubule cytoskeleton. In this mini-review, we highlight the expanding repertoire of Rab/microtubule motor protein interactions, and, in doing so, present an outline of the multiplicity of transport processes which result from such interactions.

Download Full-text

Differential regulation of CXCR2 trafficking by Rab GTPases

Blood ◽

10.1182/blood-2002-07-1965 ◽

2003 ◽

Vol 101 (6) ◽

pp. 2115-2124 ◽

Cited By ~ 79

Author(s):

Guo-Huang Fan ◽

Lynne A. Lapierre ◽

James R. Goldenring ◽

Ann Richmond

Keyword(s):

Intracellular Trafficking ◽

Chemokine Receptors ◽

Receptor Trafficking ◽

Dominant Negative ◽

Fine Tuning ◽

Rab Proteins ◽

Rab Gtpases ◽

Functional Responses ◽

Coated Pits ◽

Short Period

Intracellular trafficking of chemokine receptors plays an important role in fine-tuning the functional responses of neutrophils and lymphocytes in the inflammatory process and HIV infection. Although many chemokine receptors internalize through clathrin-coated pits, regulation of the receptor trafficking is not fully understood. The present study demonstrated that CXCR2 was colocalized with transferrin and low-density lipoprotein (LDL) after agonist treatment for different periods of time, suggesting 2 intracellular trafficking pathways for this receptor. CXCR2 was colocalized with Rab5 and Rab11a, which are localized in early and recycling endosomes, respectively, in response to agonist stimulation for a short period of time, suggesting a recycling pathway for the receptor trafficking. However, overexpression of a dominant-negative Rab5-S34N mutant significantly attenuated CXCR2 sequestration. The internalized CXCR2 was recycled back to the cell surface after removal of the agonist and recovery of the cells, but receptor recycling was inhibited by overexpression of a dominant-negative Rab11a-S25N mutant. After prolonged (4-hour) agonist treatment, CXCR2 exhibited significantly increased colocalization with Rab7, which is localized in late endosomes. The colocalization of CXCR2 with LDL and LAMP-1 suggests that CXCR2 is targeted to lysosomes for degradation after prolonged ligand treatment. However, the colocalization of CXCR2 with Lamp1 was blocked by the overexpression of a dominant-negative Rab7-T22N mutant. In cells overexpressing Rab7-T22N, CXCR2 was retained in the Rab5- and Rab11a-positive endosomes after prolonged (4-hour) agonist treatment. Our data suggest that the intracellular trafficking of CXCR2 is differentially regulated by Rab proteins.

Download Full-text

Tumour cell CD99 regulates transendothelial migration via CDC42 and actin remodelling

Journal of Cell Science ◽

10.1242/jcs.240135 ◽

2021 ◽

Author(s):

Aarren J. Mannion ◽

Adam F. Odell ◽

Alison Taylor ◽

Pamela F. Jones ◽

Graham P Cook

Keyword(s):

Cell Migration ◽

Tumour Cell ◽

Rho Gtpase ◽

Tumour Progression ◽

Xenograft Model ◽

Transendothelial Migration ◽

Tumour Cells ◽

Metastatic Progression ◽

Migratory Activity ◽

Actin Remodelling

Metastasis requires tumour cells to cross endothelial cell (EC) barriers using pathways similar to those used by leucocytes during inflammation. Cell surface CD99 is expressed by healthy leucocytes and EC and participates in inflammatory transendothelial migration (TEM). Tumour cells also express CD99 and we have analysed its role in tumour progression and cancer cell TEM. Tumour cell CD99 was required for adhesion to ECs, but inhibited invasion of the endothelial barrier and migratory activity. Furthermore, CD99 depletion in tumour cells caused redistribution of the actin cytoskeleton and increased activity of the Rho GTPase CDC42, known for its role in actin remodelling and cell migration. In a xenograft model of breast cancer, tumour cell CD99 expression inhibited metastatic progression and patient samples showed reduced expression of the CD99 gene in brain metastases compared to matched primary breast tumours. We conclude that CD99 negatively regulates CDC42 and cell migration. However, CD99 has both pro- and anti-tumour activity and our data suggests that this results in part from its functional linkage to CDC42 and the diverse signalling pathways downstream of this Rho GTPase.

Download Full-text

Hybrid Compounds & Oxidative Stress Induced Apoptosis in Cancer Therapy

Current Medicinal Chemistry ◽

10.2174/0929867325666180719145819 ◽

2020 ◽

Vol 27 (13) ◽

pp. 2118-2132 ◽

Cited By ~ 5

Author(s):

Aysegul Hanikoglu ◽

Hakan Ozben ◽

Ferhat Hanikoglu ◽

Tomris Ozben

Keyword(s):

Oxidative Stress ◽

Drug Resistance ◽

Side Effects ◽

Cancer Therapy ◽

Tumor Cells ◽

Anticancer Drugs ◽

Chemotherapeutic Agents ◽

Oxidation Reactions ◽

Hybrid Compounds ◽

Induced Apoptosis

: Elevated Reactive Oxygen Species (ROS) generated by the conventional cancer therapies and the endogenous production of ROS have been observed in various types of cancers. In contrast to the harmful effects of oxidative stress in different pathologies other than cancer, ROS can speed anti-tumorigenic signaling and cause apoptosis of tumor cells via oxidative stress as demonstrated in several studies. The primary actions of antioxidants in cells are to provide a redox balance between reduction-oxidation reactions. Antioxidants in tumor cells can scavenge excess ROS, causing resistance to ROS induced apoptosis. Various chemotherapeutic drugs, in their clinical use, have evoked drug resistance and serious side effects. Consequently, drugs having single-targets are not able to provide an effective cancer therapy. Recently, developed hybrid anticancer drugs promise great therapeutic advantages due to their capacity to overcome the limitations encountered with conventional chemotherapeutic agents. Hybrid compounds have advantages in comparison to the single cancer drugs which have usually low solubility, adverse side effects, and drug resistance. This review addresses two important treatments strategies in cancer therapy: oxidative stress induced apoptosis and hybrid anticancer drugs.

Download Full-text

Anti-Diarrheal Drug Repositioning in Tumour Cell Cytotoxicity

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190118120030 ◽

2019 ◽

Vol 19 (8) ◽

pp. 1037-1047 ◽

Cited By ~ 2

Author(s):

Jihene Elloumi-Mseddi ◽

Dhouha Msalbi ◽

Raouia Fakhfakh ◽

Sami Aifa

Keyword(s):

Side Effects ◽

Anticancer Drugs ◽

Tumour Cell ◽

Caspase 3 ◽

Drug Repositioning ◽

Brdu Incorporation ◽

Drug Concentrations ◽

Significant Difference ◽

Ic50 Values ◽

Mcf 7

Background:Drug repositioning is becoming an ideal strategy to select new anticancer drugs. In particular, drugs treating the side effects of chemotherapy are the best candidates.Objective:In this present work, we undertook the evaluation of anti-tumour activity of two anti-diarrheal drugs (nifuroxazide and rifaximin).Methods:Anti-proliferative effect against breast cancer cells (MDA-MB-231, MCF-7 and T47D) was assessed by MTT analysis, the Brdu incorporation, mitochondrial permeability and caspase-3 activity.Results:Both the drugs displayed cytotoxic effects on MCF-7, T47D and MDA-MB-231 cells. The lowest IC50 values were obtained on MCF-7 cells after 24, 48 and 72 hours of treatment while T47D and MDA-MB-231 were more resistant. The IC50 values on T47D and MDA-MB-231 cells became significantly low after 72 hours of treatment showing a late cytotoxicity effect especially of nifuroxazide but still less important than that of MCF-7 cells. According to the IC50 values, the non-tumour cell line HEK293 seems to be less sensitive to cytotoxicity especially against rifaximin. Both the drugs have shown an accumulation of rhodamine 123 as a function of the rise of their concentrations while the Brdu incorporation decreased. Despite the absence of a significant difference in the cell cycle between the treated and non-treated MCF-7 cells, the caspase-3 activity increased with the drug concentrations rise suggesting an apoptotic effect.Conclusion:Nifuroxazide and rifaximin are used to overcome the diarrheal side effect of anticancer drugs. However, they have shown to be anti-tumour drugs which make them potential dual effective drugs against cancer and the side effects of chemotherapy.

Download Full-text