Rac1-mediated Pathways Using Small Molecule Inhibitors for Cancer Treatment

Cellular Metabolism:

Normal:

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In order to function optimally and maintain homeostasis, mammalian cells utilize glucose as the main source of energy. Given that glucose is the most abundant nutrient found extracellularly, cells have developed mechanisms to import glucose and break it down, via a series of chemical reactions, to produce ATP and other intermediates to regulate various pathways and assemble macromolecules required for functioning [1, 2]. These include ribose sugars used in the production of nucleotides, glycerol and citrated to make lipids, to name a few [2].

Normal cells depend on growth factor and adhesion-mediated signaling to regulate and maintain growth, metabolism, and survival [1]. Under normal oxygen and nutrient conditions, cells utilize a process known as oxidative phosphorylation to catalyze glucose and generate APT to use as energy as this pathway results in 32 ATP molecules being produced per molecule of glucose. However, a combination of loss of function mutations in tumor suppressor genes or gain of function mutations in oncogenes, result in the altered regulation of cellular metabolism and glucose uptake in cancer cells [1]. For example, mutations in growth-factor-receptors such as EGFR, activating mutations in downstream kinases such as PI3K, or deactivating mutations their regulators such as PTEN, result in overexpression and constitutive activation various pathways, the most crucial being the regulation glucose uptake and metabolism [1, 3]. This key step has been shown to be the driver in the progression of metastatic disease and is usually associated with poor patient prognosis [1, 2].

Cancer: Increased glucose influx

It is not surprising that cancer cells highjack this pathway to serve their needs of rapid growth, proliferation, and migration. Furthermore, given the heterogeneity of cells within a tumor, the cells adapt mechanisms that provide them the best means of survival using the available  resources. In the 1920s, renowned German scientist Otto Warburg observed that cancer cells showed a significant increase in glucose consumption as compared to non-proliferating normal tissues [1]. This phenomenon, named the “Warburg Effect”, has been the subject of several studies over the past 90 years, leading to the elucidation of important metabolic characteristics in tumors and possible therapeutic targets for the treatment of cancer. Furthermore, the development of [¹⁸F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging based on the Warburg Effect, has become an invaluable tool in medical imaging [4]. Warburg described this phenomenon as “aerobic glycolysis”, in which increased glucose uptake in cancer cells results in increased glycolysis where the breakdown of glucose into lactate occurs at higher rates, even in the presence of oxygen[1, 3].

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While this process is seen in normal cells only in hypoxic conditions and is in fact detrimental to them – increased lactate levels lead to caspase-p53-mediated apoptosis, cancer cells export lactate extracellularly resulting in the acidification of the tumor microenvironment [2]. This drop in pH is a crucial step in activating proteases such as MMPs and uPARs that degrade the ECM and facilitate tumor cell migration leading to cancer metastasis [2]. Additionally, the acidic environment is toxic to the surrounding normal cells, thereby eliminating them to free up resources for the cancer cells, while providing cancer cells still using oxidative phosphorylation lactate as an easily accessible metabolite [1-3]. Therefore, while aerobic glycolysis yields fewer molecules of ATP, the byproducts of this pathway serve as important resources that can be used for non-metabolic purposes. (545 words)

[2]

GLUT4:

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Normal – Skeletal muscle/insulin

While oncogenic mutations play a myriad of roles in cancer progression, the increased influx of glucose and glycolysis is usually the result of upregulation of glucose transporters and glycolytic enzymes in tumor cells [3, 5].

 

In mammalian cells, a majority of extracellular glucose is transported across the plasma membrane via membrane associated glucose transporters (GLUTs) [6]. To date, 13 GLUT isoforms have been identified and classified according to their sequence, function, and tissue specific regulation. Of these 14, GLUT1 is the most abundantly expressed and is responsible for the basal level uptake of glucose in most cells [7, 8]. Over the past decade, however, GLUT4, a high affinity, ATP-independent glucose transporter found predominantly in insulin-sensitive tissues such as adipose tissue, skeletal, and cardiac muscle, has been of extreme interest due to the increasing incidence of Type-2 Diabetes (T2D) [6]. Furthermore, a unique characteristic of GLUT4 is that, under resting/insulin unstimulated conditions, it is mostly found in intracellular vesicles GLUT4 storage vesicles (GSVs) [9] and is rapidly transported to the plasma membrane in response to insulin stimulation [6]. Studies have shown that this acute translocation can increase plasma membrane GLUT4 levels 10-20 fold resulting in a significant influx of glucose into the cell [8].

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In short, the insulin signaling pathway is activated when insulin binds to the tyrosine kinase insulin receptor (IR) resulting in its autophosphorylation and subsequent phosphorylation of insulin receptor substrate (IRS)-1 and the recruitment and activation of class I phosphatidylinositol-3-kinase (PI3K). PI3K catalyzes the conversion of PI(4,5)P₂ to P(3,4,5)P₃ which serves as a scaffold for and activates upstream kinase PDK1, which in turn activates Akt/PKB. Akt/PKB, via the intermediate AS160, promote the transport of GLUT4 GSVs to the plasma membrane [9, 10].

Insulin Resistance

While this pathway is extremely efficient in increasing the influx of glucose, studies have shown that it is decreased by approximately 90% in insulin resistant/T2D states, despite normal production of insulin. Decrease in IR expression or its catalytic activity, or mutations in the genes regulating this pathway have been alluded to as possible causes of impaired ability of insulin to increase GLUT4 translocation [11, 12]. Given the increase in the incidence of T2D, studies have sought to find out alternative mechanisms that regulate glucose uptake, especially in skeletal muscles given that they comprise almost 40% of body mass [13] and are one of the most insulin-sensitive and glucose-dependent organs in the bogy, in addition to highly expressing GLUT4 [8].

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Exercise

While researchers have known that skeletal muscles are excellent at upregulating glucose intake in response to insulin stimulus, recent studies have shed light on an insulin-independent, contraction-dependent mechanism of upregulating GLUT4 translocation to the plasma membrane in the sarcolemma and t-tubules [7, 13, 14]. This contraction-driven uptake, achieved mainly via physical exercise, has been vital in helping patients with T2D regulate their blood glucose levels with minimal pharmaceutical intervention.

 

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Several studies have corroborated that muscle contraction, in addition to increasing GLUT4 expression, has the ability to increase GLUT4 vesicle transport to the plasma membrane in a distinct, insulin-independent manner [7, 15]. Furthermore, this increased expression and transport of GLUT4 remains high for almost 24 hours post-exercise, continuing to transport glucose into the muscle cells [15]. Several mechanisms have been suggested to explain this increase in GLUT4 expression and transport induced by muscle contraction. These include a Calcium/Calmodulin-dependent kinase (CaMK) pathway, activation of  Mitogen-activated Kinases (MAPK), increased activity of Nitric Oxide Synthase to produce Nitric Oxide (NO), increase in Reactive Oxygen Species (ROS), or the activation of cellular energy sensor AMP-activated Kinase (AMPK) pathway [7, 12, 16]. Interestingly, recent studies have shed light on the possible role of the actin cytoskeleton in mediating contraction-mediated GLUT4 vesicle transport via the activation of actin-cytoskeleton regulating small Rho GTPase, Rac1 [7, 17, 18]. While there is some overlap in pathways regulating insulin-dependent and –independent upregulation of GLUT4 and glucose uptake, studies either inhibiting these pathways with chemical/small-molecule inhibitors or over-activating them by overexpressing the proteins involved, have yielded mixed results where no one mechanism was shown to be the exclusive mediator. This is understandable given that cellular signaling is modular and several modes of regulation exist to mediate any given pathway.

Cancer

While support for the role of GLUT4 regulating glucose uptake in skeletal muscles is abundant, the evidence for its role in cancer progression is slowly emerging []. Given that tumor cells rely heavily on glucose to fuel their aerobic glycolysis, it is reasonable to look at glucose transporter expression and function in tumor cells. Not surprisingly, several groups have found GLUT1 and GLUT4 overexpressed in many tumor types, especially in insulin-independent tissues such as the mammary gland [19, 20].

Interestingly, Schwartzenberg-Bar-Yoseph et al. reported that GLUT4 was overexpressed in astrocytomas, lung cancers, most gastric carcinomas, alveolar rhabdomyosarcoma, and thyroid carcinoma. Furthermore, their finding that the tumor suppressor gene p53 played a role in downregulating GLUT4 in human osteosarcoma- and embryonal rhabdomyosarcoma-derived cell lines, indicate that GLUT4 is a major player in cancer progression. These cell lines which either lacked one or both p53 alleles, showed increased expression of GLUT4, while rescuing with wild-type p53 reversed this effect. Furthermore, p53 repressed GLUT4 expression by binding directly to its promoter region [21]. Given that p53 in mutated in almost 50% of cancers [22], this finding sheds light on how tumor cells could usurp machinery to serve their energy needs.

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Another study by Chang et al. reported that increased GLUT4 expression in the Head and neck squamous cell carcinoma (HNSCC) cell lines Ca9-22 and HSC-3-M3, significantly increased both, proliferation and migration rates [23]. Interestingly, this study revealed that this overexpression of GLUT4 was both glucose and insulin independent, suggesting that GLUT4 could be important player in the regulation of aberrant tumor metabolism and promoting invasion and thus could function as a potential biomarker for prognosis in HNSCC patients.

Another study by Medina et al. showed that the steroid hormones estrogen and progesterone, commonly used as oral contraceptives and hormone replacement therapy, increased the expression of GLUT4 in infiltrating ductal carcinoma breast cancer cell line ZR-75-1. This corresponded to higher glucose uptake and higher proliferation rates, suggesting a strong relationship between GLUT4 expression and progression of cancer [24].

While the above studies looked at GLUT4 expression in various cancer cell lines, Garrido et al, in addition to looking at expression levels in MCF-7 breast cancer cell line, also sought to elucidate if there was also an increase in GLUT4 translocation to the plasma membrane upon exposure to 17B-estradiol (E2) [20]. While it is known that E2 enhances the PI3K-Akt signaling pathway in these cells, they surprisingly found increased presence of GLUT4 at the plasma membrane in E2 treated cells as compared to untreated, potentially mediated by activation of the PI3K-Akt pathway. Building on this study, they also reported that downregulation of GLUT4 in the MDA-MB-231 triple-negative and MCF-7 breast cancer cell lines resulted in decreased cell proliferation and migration, and induced apoptosis. Furthermore, silencing GLUT4 expression resulted in a metabolic switch to oxidative phosphorylation, which in the absence of oxygen, resulted in cell death [25].

 

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Taken together, these results suggest a critical role for GLUT4 expression in the progression of cancer and inducing metastasis. While GLUT4 has been of significant interest in the progression of T2D, given the propensity for tumor cells to switch to aerobic glycolysis utilizing high levels of glucose to grow, proliferate, and migrate, GLUT4 also emerges as a prime candidate for study and therapeutic intervention. (1540 words)

 

Rac1:

Normal

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As mentioned earlier, GLUT4 is unique among the GLUTs in that it is mainly stored in intracellular vesicles in resting/unstimulated states and basal levels at the plasma membrane are maintained via a recycling pathway [17, 26]. As such, concurrent to increased expression of GLUT4, its transport to the plasma membrane is required in order for it to function as a glucose transporter and increase glucose transport into the cell.

Given the significant gaps in the understanding of the complex processes involved in vesicle trafficking inside cells, GLUT4 trafficking has been the subject of interest for many years to fill some of these gaps [9] possibly due of the feasibility of using the insulin signaling pathway.

Interestingly, in the insulin signaling pathway mentioned earlier, PI3K activation serves as a branching point post-activation – either activating Akt/PKB or the small Rho GTPase Rac1 (Ras-related C3 botulinum toxin substrate 1) downstream to promote glucose uptake [9, 27]. In insulin-stimulated skeletal muscles, inhibition of each pathway individually only moderately affected glucose uptake while inhibiting both branches abolished it [28-30]. This suggests that while the two branches might work independently downstream of PI3K activation, they are both indispensible to the insulin response in normal skeletal muscles [9]. As such, in the above mentioned study by Garrido et al looking at the PI3K-Akt pathway[20], it is quite possible that Rac1 was also involved in GLUT4 translocation.

 

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Exercise

Given the reduced response to insulin in T2D patients, insulin-independent uptake in glucose is vital to not only maintain healthy blood-glucose levels, but also meet the energy requirements of cells. Recently, studies looking at the effect of physical endurance exercise on glucose uptake in T2D have implicated Rac1, a known regulator of actin cytoskeleton remodeling, in muscle contraction-mediated glucose uptake at attributed the increased actin remodeling that occurs as a result of the shortening-relaxation of muscle fibers during exercise to Rac1-mediated processes [26, 28, 31, 32]. In vivo studies using mice with muscle specific knockout of Rac1 showed significant reduction in glucose uptake upon muscle contraction. Furthermore, disrupting the actin cytoskeleton or inhibiting actin remodeling also showed a similar phenotype, possibly implicating both Rac1 and cortical actin remodeling as critical components of contraction stimulated glucose uptake  [9, 14, 31, 33].

Recent studies have tried to elucidate this role of Rac1-regulated cytoskeleton remodeling in GLUT4 transport during contraction-exercise. A study by Sylow et al reported that Rac1 is activated by contraction/stretch-induced mechanical stress in muscle cells and increased glucose transport [33]. Furthermore, inhibiting Rac1, disrupting tension development, or disrupting the cytoskeleton, abrogated this response, indicating that Rac1 plays a role in mediating the mechanical stress   induced glucose uptake, possibly via increasing GLUT4 exocytosis. Follow-up studies by this group confirmed this result and provided strong evidence for a contraction-induced upregulation of Rac1-mediated GLUT4 transport to the plasma membrane [30, 31].

While increased glucose uptake as a result of muscle contraction/stretch response has been known as early 2003, and various mechanisms proposed for this phenomenon, the Rac1-mediated mechanism has only recently been elucidated, albeit not fully. In 2003, The Jarrett group reported that in skeletal muscles, the dystrophin glycoprotein complex (DGC), comprised of proteins including dystrophin, dystroglycans, and syntrophins, acted as a mechanotransducer, connecting the ECM molecule laminin to the actin cytoskeleton. In a subsequent study, they showed that laminin binding recruited and activated Rac1 via Src family kinases. This triggered downstream Rac1 signaling, possibly recruiting and activating PAK1 and other kinases [9, 34, 35].

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Several groups studying the role of Rac1 in cell migration revealed that once activated, Rac1 activates actin nucleating factors neuronal Wiskott–Aldrich syndrome protein (nWASP) and WASP-family verprolin-homologous protein (WAVE) which then activate Arp2/3 complex, resulting in actin filament polymerization and branching. Subsequent activation of PAK1 and the actin severing protein cofillin, leads to actin “treadmilling” and dynamic cytoskeleton remodeling, resulting in cell migration [36, 37].

Interestingly, this pathway was also found to be responsible for insulin-stimulated GLUT4 translocation and glucose uptake in skeletal muscles [9]. However, inhibiting the various proteins – Rac1, PAK1, WAVE, nWASP in insulin-independent, contraction-stress stimulated muscle cells, abrogated GLUT4 transport and glucose uptake. This suggested that mechanical-stress induced glucose uptake also functioned via the Rac1-mediated GLUT4-translocation pathway [17, 26, 31]. Moreover, the cortical actin filaments of the cytoskeleton serve as tracks for the myosin motor protein Myo5 to guide and transport GLUT4 vesicles to the plasma membrane [28]. Furthermore, Rac1-mediated dynamic actin remodeling has also shown to be required for keeping the transported GLUT4 vesicles beneath the plasma membrane and promote vesicle fusion [38]. The results from these studies reveal the important role of Rac1 and its downstream signaling mediated cytoskeleton remodeling in regulating both insulin- and contraction-stress stimulated glucose uptake in skeleton muscle mainly via the translocation of GLUT4 vesicles to the plasma membrane.

 

Cancer:

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It is not surprising that Rac1 is commonly found to be overexpressed in cancers, given its ability to promote tumor growth, invasion, and metastasis of tumor cells [37]. Moreover, Rac1 is found to be overexpressed especially in cancers with invasive pathologies, and is potentially involved in their often-displayed increased actin remodeling [37]. In addition to the role of Rac1 in regulating cell migration, Rac1 is also involved in forming and maintaining cell-cell adhesions, a function that is disregulated in invasive tumor cells. Furthermore, Rac1 has been shown to interact with integrins – molecules that connect the ECM to the cytoskeleton similar to DGC in muscle cells, and regulate cell adhesion and migration [37]. This intergrin-Rac1-mediated migration involves actin remodeling leading to plasma membrane extension and the formation of structures known as lemellipoida at the leading edge to move the cell forward [36].

The above mentioned processes of actin remodeling, forming cell-cell adhesions, and migration and critical process that are disregulated in many cancers, putting Rac1 at the forefront of studies looking to target pathways involved in promoting tumor migration and invasion. A study by Yue et al. reported that a gain of function mutation in p53 bound to, and through SUMOylation, activated Rac1, promoting tumor growth and metastasis in various human cancer cells including colorectal cancer, prostate cancer, and breast cancer. Additionally, p53 also blocked the negative regulator of Rac1, SENP-1, thereby keeping it in the active state [39]. While this study did not look into the effects on cell metabolism, it sheds further light on the effects of over activated Rac1 in cancer cells, and given the need for increased glucose uptake in proliferating cells, Rac1 could quite possibly aid in upregulating GLUT4 transport to meet this need.

Another recent study by Liu et al. showed that in tissue samples from patients diagnosed with Invasive ductal carcinoma, not otherwise specified (IDC-NOS),  increased expression of Rac1 correlated with increased metastasis to the lymph node and poor patient prognosis [40]. Given the role of Rac1 in maintaining cell polarity, they suggested that this was possibly due to Rac1-mediated partial reverse of cell polarity, resulting in an invasive phenotype.

Gonzalez et al., while studying the role of Rac1 in imparting Tamoxifen resistance in treatment of ER-positive breast cancer using the MCF7 breast cancer cell line, found that expressing a constitutively active form of Rac1 in these cells, enhanced Tamoxifen resistance, and increased cell proliferation, independent of estrogen stimulation. Additionally, these cells also displayed increased lamellipodia formation and migration, both processes known to be regulated by Rac1. Furthermore, they also implicated the role of Rac1 downstream molecule PAK1 in reducing Tamoxifen resistance by phosphorylating and activating ER. However, inhibiting Rac1-PAK1 signaling  using 1A-116, a Rac1 specific inhibitor developed in their lab, increased Tamoxifen sensitivity and significantly reduced proliferation [41].

Taken together, results from the above mentioned studies point towards a strong correlation between increased Rac1 activity and the progression of metastatic disease. While they did not look into the specific mechanisms involved in Rac1-mediated tumorigenesis, it is likely that Rac1-mediated regulation of the actin cytoskeleton remodeling plays a major role. Additionally, given that Rac1 is implicated in cell growth, proliferation, and migration, all highly energy-dependent processes, the role of GLUT4 in increasing glucose uptake cannot be ruled out, given that GLUT4 has been found to be upregulated in many tumors.

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Conclusions

Given the co-existence and activation of multiple pathways simultaneously in the progression of cancer, combination treatments targeting multiple molecules and pathways have become the standard mode of cancer treatment. This review elucidates a potentially novel mechanism that invasive cancers could use to gain selective and proliferative advantage, in addition to developing resistance to chemotherapeutic drugs. Migrating cells experience significant mechanical stress as they remodel and move through the ECM and several studies have shown that a consequence of this is the dynamic remodeling of the actin cytoskeleton. Given the role of Rac1 in mediating this remodeling taken together with disregulated Rac1 activity and GLUT4 expression, the phenomenon observed in contraction-stimulated skeletal muscles could potentially be at play in promoting tumor metastasis.

While studies inhibiting Rac1-mediated pathways using small molecule inhibitors have shown promise in reducing tumor growth and invasion in vitro, these results did not translate to success in animal models. This could possibly be due to redundancy in the signaling pathways, the presence of compensatory feedback mechanisms, the inability of the inhibitor to completely abrogate its target molecule activity, or weak target specificity [37, 42]. Furthermore, not taking into consideration the impact of the ECM on the tumor cell and vice-versa, could conceal potential mechanisms cancer cells could utilize to gain selective and reproductive advantage.

Interestingly, overexpression of wild-type or constitutively active Rac1 in skeletal muscle resulted in the increased presence of GLUT4 on the plasma membrane in muscle cells, even in the absence of insulin stimulation [28]. As such, given the usually hypoxic and insulin-deprived microenvironments of most tumors, it is not farfetched to hypothesize that migrating cancer cells utilize this Rac1-mediated GLUT4 transport pathway to increase glucose influx in order to serve their high metabolic needs in addition to using the byproduct macromolecules as “weapons” to gain survival advantage. Confirmation and elucidation of the role of the Rac1-GLUT4 mechanism in promoting tumor cell invasion and metastasis could potentially open new avenues to target invasive cancers and improve patient outcomes.

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