Oncotarget

Research Papers:

Polyisoprenylated cysteinyl amide inhibitors deplete singly polyisoprenylated monomeric G-proteins in lung and breast cancer cell lines

Nada Tawfeeq, Jassy Mary S. Lazarte, Yonghao Jin, Matthew D. Gregory and Nazarius S. Lamango _

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Oncotarget. 2023; 14:243-257. https://doi.org/10.18632/oncotarget.28390

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Abstract

Nada Tawfeeq1,2,*, Jassy Mary S. Lazarte1,*, Yonghao Jin1, Matthew D. Gregory1 and Nazarius S. Lamango1

1 Florida A&M University College of Pharmacy Pharmaceutical Sciences, Institute of Public Health, Tallahassee, FL 32307, USA

2 Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman bin Faisal University, Dammam, Eastern Province, Kingdom of Saudi Arabia

* These authors contributed equally to this work and share first authorship

Correspondence to:

Nazarius S. Lamango, email: [email protected]

Keywords: PCAIs; G-proteins; KRAS; RHOA; RAC1

Received: February 17, 2023     Accepted: March 08, 2023     Published: March 24, 2023

Copyright: © 2023 Tawfeeq et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Finding effective therapies against cancers driven by mutant and/or overexpressed hyperactive G-proteins remains an area of active research. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) are agents that mimic the essential posttranslational modifications of G-proteins. It is hypothesized that PCAIs work as anticancer agents by disrupting polyisoprenylation-dependent functional interactions of the G-Proteins. This study tested this hypothesis by determining the effect of the PCAIs on the levels of RAS and related monomeric G-proteins. Following 48 h exposure, we found significant decreases in the levels of KRAS, RHOA, RAC1, and CDC42 ranging within 20–66% after NSL-YHJ-2-27 (5 μM) treatment in all four cell lines tested, A549, NCI-H1299, MDA-MB-231, and MDA-MB-468. However, no significant difference was observed on the G-protein, RAB5A. Interestingly, 38 and 44% decreases in the levels of the farnesylated and acylated NRAS were observed in the two breast cancer cell lines, MDA-MB-231, and MDA-MB-468, respectively, while HRAS levels showed a 36% decrease only in MDA-MB-468 cells. Moreover, after PCAIs treatment, migration, and invasion of A549 cells were inhibited by 72 and 70%, respectively while the levels of vinculin and fascin dropped by 33 and 43%, respectively. These findings implicate the potential role of PCAIs as anticancer agents through their direct interaction with monomeric G-proteins.


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