ecancermedicalscience

Angiogenesis is essential for solid tumor growth, therapeutic resistance and metastasis, the latest accounting for 90% of cancer deaths. Although angiogenesis is essential for the malignant transformations in solid tumors and therefore is an attractive target, few drugs are available that block tumor angiogenesis. The focus has been to block signaling by receptor tyrosine kinases (RTKs), such as for vascular endothelial growth factor (VEGF), whose activation abrogate apoptosis and promote angiogenesis. The polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed to modulate aberrant polyisoprenylated small G-proteins such as mutant Ras whose constitutive activation promotes RTKs signaling. Since polyisoprenylation is essential for protein-protein interactions and functions of G-proteins, we hypothesized that the PCAIs would disrupt the monomeric G-protein signaling thereby effectively inhibiting angiogenesis. In this study we determined the effects of PCAIs on human umbilical vein endothelial cells (HUVEC) tube formation, cell viability, cell migration and invasion as well as in vivo using the chick chorioallantoic membrane (CAM) and zebrafish models. At sub- to low micromolar concentrations, the PCAIs inhibit the native and VEGF-stimulated cell migration and invasion as well as tube formation and angiogenesis in CAM and zebrafish embryos. The concentrations that block the angiogenic processes were lower than those that induce cell death. Since angiogenesis is essential for tumor growth but otherwise limited to wound healing, feeding fat cells and uterine wall repair in adults, it is conceivable that these compounds can be developed into safer therapeutics for cancers and retinal neovascularization that leads to loss of vision.

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The antiangiogenic effects of polyisoprenylated cysteinyl amide inhibitors in HUVEC, chick embryo and zebrafish is dependent on the polyisoprenyl moiety

Nkembo

Ntantie

Salako

et al. 2016

Oncotarget

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Polyisoprenylated Cysteinyl Amide Inhibitors: A Novel Approach to Controlling Cancers with Hyperactive Growth Signaling

Lamango

Nkembo

Ntantie

et al. 2021

CMC

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: Aberrant activation of monomeric G-protein signaling pathways drives some of the most aggressive cancers. Suppressing these hyperactivities has been the focus of efforts to obtain targeted therapies. Polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed in various cancers. Its inhibition induces the death of cancer cells that harbor the constitutively active K-Ras proteins. Furthermore, the viability of cancer cells driven by factors upstream of KRas, such as overexpressed growth factors and their receptors or the mutationally-activated receptors is also susceptible to PMPMEase inhibition. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were thus designed to target cancers with hyperactive signaling pathways involving the G-proteins. The PCAIs were however poor inhibitors of PMPMEase, with Ki values ranging from 3.7 to 20 µM. On the other hand, they inhibited cell viability, proliferation, colony formation, induced apoptosis in cells with mutant K-Ras and inhibited cell migration and invasion with EC50 values of 1 to 3 M. HUVEC tube formation was inhibited at submicromolar concentrations through their disruption of actin filament organization. At the molecular level, the PCAIs at 2 to 5 M depleted monomeric G-proteins such as K-Ras, RhoA, Cdc42 and Rac1. The PCAIs also deplete vinculin and fascin that are involved in actin organization and function while disrupting vinculin punctates in the process. These demonstrate a polyisoprenylation-dependent mechanism that explains the observed PCAIs’ inhibition of the proliferative, invasive and angiogenic processes that promote both tumor growth and metastasis.

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The Hypervariable Region of K-Ras4B Governs Molecular Recognition and Function

Abdelkarim

Banerjee

Grudzien

et al. 2019

IJMS

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The flexible C-terminal hypervariable region distinguishes K-Ras4B, an important proto-oncogenic GTPase, from other Ras GTPases. This unique lysine-rich portion of the protein harbors sites for post-translational modification, including cysteine prenylation, carboxymethylation, phosphorylation, and likely many others. The functions of the hypervariable region are diverse, ranging from anchoring K-Ras4B at the plasma membrane to sampling potentially auto-inhibitory binding sites in its GTPase domain and participating in isoform-specific protein–protein interactions and signaling. Despite much research, there are still many questions about the hypervariable region of K-Ras4B. For example, mechanistic details of its interaction with plasma membrane lipids and with the GTPase domain require further clarification. The roles of the hypervariable region in K-Ras4B-specific protein–protein interactions and signaling are incompletely defined. It is also unclear why post-translational modifications frequently found in protein polylysine domains, such as acetylation, glycation, and carbamoylation, have not been observed in K-Ras4B. Expanding knowledge of the hypervariable region will likely drive the development of novel highly-efficient and selective inhibitors of K-Ras4B that are urgently needed by cancer patients.

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ecancermedicalscience

Cited by 3 publications

References 43 publications

The antiangiogenic effects of polyisoprenylated cysteinyl amide inhibitors in HUVEC, chick embryo and zebrafish is dependent on the polyisoprenyl moiety

The antiangiogenic effects of polyisoprenylated cysteinyl amide inhibitors in HUVEC, chick embryo and zebrafish is dependent on the polyisoprenyl moiety

Polyisoprenylated Cysteinyl Amide Inhibitors: A Novel Approach to Controlling Cancers with Hyperactive Growth Signaling

The Hypervariable Region of K-Ras4B Governs Molecular Recognition and Function

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