1.5 Drugs targeting the Rab prenylation pathway
1.5.1 Prenylation pathway
Prenylation of Rab proteins is the essential lipid modification step that begins the membrane trafficking cycle. It is a crucial post-translational modification that allows the stable attachment of Rab proteins to the membrane by increasing hydrophobicity to be able to insert into the lipid bilayer (Maltese, Wilson and Erdman, 1996).
As depicted in Figure 7, the Rab cycle starts with a Rab protein that is GDP bound, in its inactive state. It binds to Rab escort protein (REP), which directs it to the RGGT, where the Rab protein is isoprenylated by addition of geranylgeranyl pyrophosphate (GPP) group or farnesyl pyrophosphate (FPP) onto the cysteine. The REP then transports the prenylated Rab protein to its target membrane where guanine exchange factor (GEF) exchanges the GDP to GTP to activate it. The Rab protein can then associate with its effector protein, specific to the Rab type, to carry out functions such as vesicle formation, movement of the vesicle or tethering a vesicle to a membrane. A GTPase activating protein (GAP) hydrolyses GTP to GDP, by losing an inorganic phosphate group, to inactivate it once again. A guanine nucleotide dissociation inhibitor (GDI) removes the attachment of the Rab protein from the membrane. The GDI dissociation factor (GDF) is used to dissociate the Rab protein from the GDI for recycling (Hutagalung and Novick, 2011). Rab prenylation is vital for Rab function, thus targeting Rab prenylation might be a plausible method to inhibit melanoma progression, given the importance of Rab proteins in melanoma. 1.5.2 Statins in cancer Statins are predominately used clinically to treat high low-density lipoprotein (LDL) cholesterol levels in cardiovascular diseases, as well as reducing atherosclerotic plaques and reducing cardiovascular related deaths (Hindler et al., 2006). …show more content…
However, they are also of interest in cancer as they have been shown to affect its many aspects (Pich et al., 2013). The mechanism that underpins the effectiveness of statins for hypercholesterolemia is the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme that catalyses the formation of mevalonic acid from HMG-CoA. Mevalonic acid is a precursor of cholesterol, and therefore inhibiting HMG-CoA reductase is very effective for inhibiting cholesterol synthesis. Mevalonic acid is also of particular interest in relation to Rab GTPases because it is also the precursor to isoprenyl groups FPP and GPP, which are essential for prenylation (Hindler, 2006). Once activated with attachment of these groups, intracellular transport and downstream signal transduction can occur, leading to transcription of genes that are favourable to differentiation and proliferation (Gazzerro et al., 2011). This highlights the pleiotropic effects of statins. Figure 8 shows the importance of HMG-CoA reductase in the mevalonate pathway, influencing both cholesterol synthesis and prenylation of Rab proteins. The use of statins depletes cells of mevalonate as well as isoprenoids. Statins have been shown to inhibit tumour growth in a variety of cancers such as pancreatic carcinoma, colon adenocarcinoma, neuroblastoma and melanoma, by a variety of mechanisms. Statin-mediated apoptosis could possibly be due to an increased expression of pro-apoptotic proteins and a decrease in anti-apoptotic proteins (Hindler, et al. 2006). Statins also have the ability to repress tumour metastases by disrupting and inhibiting crucial steps of metastasis, such as invasion of BM and migration through ECM (Hindler, et al. 2006). However, not all studies have confirmed the link between the use of statins and the reduction of tumour metastases. A variety of statins have been tested, including Atorvastatin and Lovastatin, which have been proven effective in differing tumour cell types (Hindler, et al. 2006). However, there are conflicting results that show anti-carcinogenic effects. Only higher doses than that used in hypercholesterolemia have been implicated with anti-carcinogenic effects (Hindler, et al.2006). Correlation analysis studies have been carried out to investigate the association between risks of cancer with the administration of statins for lowering cholesterol levels. Hindler, et al. summarises particular studies that investigated whether there is a correlation between cancer incidence and statin use. A study by Sacks, et al. in 1996, found that incidence of breast cancer increased with the use of pravastatin. Conflicting with this is a study by ALLHAT Collaborative Research Group in 2002, which found no significance between cancer incidence with and without the use of pravastatin. Overall, some tumour types are
1.5.1 Prenylation pathway
Prenylation of Rab proteins is the essential lipid modification step that begins the membrane trafficking cycle. It is a crucial post-translational modification that allows the stable attachment of Rab proteins to the membrane by increasing hydrophobicity to be able to insert into the lipid bilayer (Maltese, Wilson and Erdman, 1996).
As depicted in Figure 7, the Rab cycle starts with a Rab protein that is GDP bound, in its inactive state. It binds to Rab escort protein (REP), which directs it to the RGGT, where the Rab protein is isoprenylated by addition of geranylgeranyl pyrophosphate (GPP) group or farnesyl pyrophosphate (FPP) onto the cysteine. The REP then transports the prenylated Rab protein to its target membrane where guanine exchange factor (GEF) exchanges the GDP to GTP to activate it. The Rab protein can then associate with its effector protein, specific to the Rab type, to carry out functions such as vesicle formation, movement of the vesicle or tethering a vesicle to a membrane. A GTPase activating protein (GAP) hydrolyses GTP to GDP, by losing an inorganic phosphate group, to inactivate it once again. A guanine nucleotide dissociation inhibitor (GDI) removes the attachment of the Rab protein from the membrane. The GDI dissociation factor (GDF) is used to dissociate the Rab protein from the GDI for recycling (Hutagalung and Novick, 2011). Rab prenylation is vital for Rab function, thus targeting Rab prenylation might be a plausible method to inhibit melanoma progression, given the importance of Rab proteins in melanoma. 1.5.2 Statins in cancer Statins are predominately used clinically to treat high low-density lipoprotein (LDL) cholesterol levels in cardiovascular diseases, as well as reducing atherosclerotic plaques and reducing cardiovascular related deaths (Hindler et al., 2006). …show more content…
However, they are also of interest in cancer as they have been shown to affect its many aspects (Pich et al., 2013). The mechanism that underpins the effectiveness of statins for hypercholesterolemia is the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme that catalyses the formation of mevalonic acid from HMG-CoA. Mevalonic acid is a precursor of cholesterol, and therefore inhibiting HMG-CoA reductase is very effective for inhibiting cholesterol synthesis. Mevalonic acid is also of particular interest in relation to Rab GTPases because it is also the precursor to isoprenyl groups FPP and GPP, which are essential for prenylation (Hindler, 2006). Once activated with attachment of these groups, intracellular transport and downstream signal transduction can occur, leading to transcription of genes that are favourable to differentiation and proliferation (Gazzerro et al., 2011). This highlights the pleiotropic effects of statins. Figure 8 shows the importance of HMG-CoA reductase in the mevalonate pathway, influencing both cholesterol synthesis and prenylation of Rab proteins. The use of statins depletes cells of mevalonate as well as isoprenoids. Statins have been shown to inhibit tumour growth in a variety of cancers such as pancreatic carcinoma, colon adenocarcinoma, neuroblastoma and melanoma, by a variety of mechanisms. Statin-mediated apoptosis could possibly be due to an increased expression of pro-apoptotic proteins and a decrease in anti-apoptotic proteins (Hindler, et al. 2006). Statins also have the ability to repress tumour metastases by disrupting and inhibiting crucial steps of metastasis, such as invasion of BM and migration through ECM (Hindler, et al. 2006). However, not all studies have confirmed the link between the use of statins and the reduction of tumour metastases. A variety of statins have been tested, including Atorvastatin and Lovastatin, which have been proven effective in differing tumour cell types (Hindler, et al. 2006). However, there are conflicting results that show anti-carcinogenic effects. Only higher doses than that used in hypercholesterolemia have been implicated with anti-carcinogenic effects (Hindler, et al.2006). Correlation analysis studies have been carried out to investigate the association between risks of cancer with the administration of statins for lowering cholesterol levels. Hindler, et al. summarises particular studies that investigated whether there is a correlation between cancer incidence and statin use. A study by Sacks, et al. in 1996, found that incidence of breast cancer increased with the use of pravastatin. Conflicting with this is a study by ALLHAT Collaborative Research Group in 2002, which found no significance between cancer incidence with and without the use of pravastatin. Overall, some tumour types are