Rabs Mediated Membrane Trafficking in Cancer Progression

Ras-associated binding (Rab) GTPases control diverse stages of endo and exocytic pathways. Functional impairments of Rabs and its associated proteins have been implicated in many hereditary and neurological diseases. Although Rabs are not classically considered as oncoproteins, many Rabs have been involved in tumor progression/proliferation and its aggressiveness. Rabs contribute to tumor cell migration, invasion of cancer cell to extracellular matrix (ECM) and modiﬁcation of tumor microenvironment through modulation in integrin trafficking, exosomal and protease secretions. In the present review, current knowledge about the pathogenesis and tumor progression of some Rabs (Rab27, 25 & 21) has been discussed.

guanine nucleotide exchange factors (GEFs), which facilitate the activation of Rabs by exchanging GDP with GTP; GTPase activating proteins (GAPs), which hydrolyze GTP into GDP, rendering Rabs into inactivated state; and guanine nucleotide dissociation inhibitors (GDIs), which act as negative regulators. GDI maintains the cytosolic form of Rab proteins by interacting with the isoprenylated C-terminal of Rabs [5].
Functions of other effectors of Rab proteins, e.g. SNAREs (Soluble N-ethylmaleimide sensitive factor attachment protein receptor), motor proteins and tethering factors, are summarized in figure 1. Rab escort protein (REP) presents Rabs to geranylgeranyltransferase which adds isoprenoid moieties to one or two cysteine resides on the C-terminal of Rab proteins. This process helps to attain the attachment capacity [6]. Dysregulation in Rabs function by mutations in them and their effectors may alter the vesicular transport system which can contribute to developing tumorigenesis and many inherited disorders such as choroideremia and Griscelli syndrome [7].
Recent advancements in understanding cancer progression enable us to overview the current knowledge about the role of Rabs mediated endosomal trafficking in cancer, which will be the focus of this review.

Role of Rabs in pathophysiology
Compartmentalization of organelles and the impermeable nature of plasma membrane hinder many cell sustaining molecules to enter the cell. Exchange of molecules between these organelles is mediated by vesicular transport; a series of specific steps that facilitate the accurate delivery of materials between intracellular organelles by vesicles. Rab proteins, being specific to each membranous compartment, assist in endocytic and exocytic membrane transport. Efficient trafficking is essential, because the incorrect localization of molecules can cause disastrous and even fatal effects to the cell [8,9]. Some Rabs are tissue or cell specific, while most of the Rabs express ubiquitously and may participate in more than one step in transport. For example, Rab1 has been documented in early intra-Golgi transport as well as in vesicle budding from ER to Golgi [10]. Rab27a is involved in the exocytosis of lytic granules from cytotoxic T lymphocytes (CTL) [11] and in the peripheral distribution of intracellular vesicles called melanosomes, which are required for normal skin and hair colour development. Loss of function mutation in Rab27a is responsible for an autosomal recessive disorder of diluted pigments in skin and hair called Griscelli Syndrome subtype 2 [12, 13].
MYO5A gene encodes a motor protein myosin Va which is responsible for melanosomal arrest and its peripheral accumulation at the distal ends of melanocytes' dendrites, from where melanosomes can be transferred to Digital Medicine and Health Technology 2/11
Amplification in chromosome 1q is associated with breast and ovarian cancers, makes Rab25 a tumor suppressor [44].
As described earlier, Rab25 can activate growth promoting pathway which may stimulate cellular proliferation in cancer cells. Similarly knockdown of Rab25 can reduce metastatic potential in cancer cells due to decrease in phospho-Akt levels, for example, in bladder cancer cells [45] glioblastoma multiforme cells [46], breast cancer cells and ovarian cancer cells [28]. This phenomenon supports the potential involvement of PI3K pathway in facilitating Rab25 activity. Inhibition of Rab25 in hepatocellular carcinoma cells was reported to block cell growth rate possibly due to the depletion of AKT phosphorylation, Wnt signaling pathway and its target genes (MMP7, cyclin D and c-myc) [47].
Rab25 has been documented in the alternation of expression of apoptotic molecules; where Rab25 was found to reduce pro-apoptotic proteins BAX and BAK in ovarian cancer [28], and its knockdown tends to reduce anti-apoptotic molecule Bcl-2 in tobacco carcinogen-induced lung cancer [48]. Hence, it can be concluded that, the epithelial-specific protein, Rab25, boosts cancer progression by stimulating growth promoting signaling pathways and suppressing apoptotic cell death.
With regard to the tumor suppressive nature of Rab25, it was speculated that the loss of Rab25 may cause imbalance in the distribution of some important cargoes in membrane trafficking that augment colon carcinogenesis, as genetic deletion of Rab25 in mice having intestinal and colonic neoplasms showed accelerated tumorigenesis [41]. Similarly, the expression of Rab25 was also considerably reduced in clinical specimens of esophageal squamous cell carcinoma (ESCC). Akin to the most common reason behind the downregulation of many tumor suppressors; the suppression of Rab25 in ESCC was also due to its promoter hypermethylation.
Moreover, stable overexpression of Rab25 not only decreased phosphorylation of FAK and c-Raf, which reduced downstream signaling of MAPK/ERK, but also minimized invasion and angiogenesis in tumor cells [42]. In human ovarian cancer cell line (A2780), increases in cellular mobility have been observed by localization of integrin-recycling vesicles to plasma membrane by Rab25 [49].

Rab21
Rab21 was initially cloned and sequenced by  Diversified mechanism of these molecular switches in tumor progression can be used in elucidating novel therapeutic targets and prognostic biomarkers in different cancers. Developing Rab specific inhibitors, which are unavailable presently, may be useful to investigate the Rabs targeted molecules that can improve cancer therapy.

Conclusion
The mechanism involved in the overexpression of Rab21, 25 and 27 in cancer progression is another area to study that can produce new methods for cancer prevention. Currently, increase in mRNA levels due to copy number

Conflict of interest
The author has no competing interest to declare that may directly or indirectly affect the content of this article.
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