image: Figure 10: PCAIs treatment collapses actin filaments and delocalizes focal adhesion proteins. Cells were grown in 8-well ibidi μ-slides overnight and treated with the respective concentrations of PCAIs for 48 h, then fixed and permeabilized. Images of the cells treated with 0 and 5 μM NSL-YHJ-2-27 are shown at higher magnification whereby yellow arrows indicating retracting lamellipodia indicative of collapsing actin filaments. (A) Triplicates of the fixed cells were stained with Alexa Fluor™ 568 Phalloidin for actin filaments. Yellow arrows indicate retracting lamellipodia indicative of the collapsing actin filaments (magnified images). (B) Vinculin punctates were probed using vinculin antibody and visualized using rabbit IgG Alexa Fluor 555 conjugate. White arrows indicate vinculin punctates. (C) Fascin was probed with fascin antibody and visualized using mouse IgG Alexa Fluor 488. White arrows indicate defined fascin spots. Images were captured using Keyence BX-X800 microscope at 40X magnification. (D) Cells treated for 48 h with the indicated concentrations of NSL-YHJ-2-27 or 5 μM of the non-farnesylated PCAIs analog, NSL-YHJ-2-62. Lysis of the cells and analysis by western blotting for vinculin and fascin were conducted as described in the methods. Western blot images and plots of chemiluminescence intensities of the bands following quantification using Image Lab Software normalized against GAPDH against concentration. Data are representative of three independent experiments. Statistical significance (**p < 0.01 in relation to the negative control, 0 μM) was determined by one-way ANOVA with post hoc Dunnett’s test.
Credit: Copyright: © 2025 Lazarte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
“The ability of PCAIs to mitigate various cancer hallmarks in the various cancer cell lines has been well established.”
BUFFALO, NY – August 13, 2025 – A new research paper was published in Volume 16 of Oncotarget on July 29, 2025, titled “PCAIs stimulate MAPK, PI3K/AKT pathways and ROS-Mediated apoptosis in aromatase inhibitor-resistant breast cancer cells while disrupting actin filaments and focal adhesion.”
In this study, led by first author Jassy Mary S. Lazarte and corresponding author Nazarius S. Lamango from Florida A&M University College of Pharmacy and Pharmaceutical Sciences, researchers investigated a new class of compounds called polyisoprenylated cysteinyl amide inhibitors (PCAIs) as a potential treatment for aromatase inhibitor (AI) therapy resistant breast cancer. Aromatase inhibitors are a common treatment for estrogen receptor-positive (ER+) breast cancer, but many patients eventually develop resistance, leaving fewer therapeutic options.
The study focused on a PCAI compound called NSL-YHJ-2-27, which was tested in long-term letrozole-treated breast cancer cells (LTLT-Ca), an experimental model of AI therapy resistance. NSL-YHJ-2-27 activated two major signaling pathways, MAPK and PI3K/AKT. Although these pathways typically support cancer cell survival, their overstimulation by PCAIs led to increased oxidative stress, damaging the cells and inducing cell death by apoptosis. The compound also reduced levels of RAC1 and CDC42, proteins involved in maintaining cell shape and movement. These alterations resulted in cytoskeletal disruption and reduced structural integrity, making the cancer cells more vulnerable and less capable of spreading. Importantly, the effects of NSL-YHJ-2-27 persisted after the compound was removed, suggesting long-term control over AI resistant cancer cells may be possible.
“PCAIs inhibited cell proliferation and colony formation by 95% and 74%, respectively, increased active caspase 7 and BAX 1.5-fold and 56%, respectively. NSL-YHJ-2-27 (10 μM) induced LTLT-Ca spheroid degeneration by 61%.”
As a new class of targeted molecules, PCAIs represent an innovative approach distinct from traditional endocrine therapies. Their ability to affect multiple cellular mechanisms simultaneously makes them promising candidates for future drug development.
Overall, this study presents a promising new approach for treating AI therapy-resistant breast cancer. By targeting cellular pathways that support survival and mobility, PCAIs like NSL-YHJ-2-27 could provide a novel strategy to manage advanced or resistant forms of the disease. Further research, including in vivo studies and clinical trials, will be essential to confirm these findings and evaluate their therapeutic potential.
Continue reading: DOI: https://doi.org/10.18632/oncotarget.28759
Correspondence to: Nazarius S. Lamango – nazarius.lamango@famu.edu
Keywords: cancer, PCAIs, ROS, MAPK, PI3K/AKT, LTLT-Ca cells
Click here to sign up for free Altmetric alerts about this article.
About Oncotarget:
Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.
Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).
To learn more about Oncotarget, visit Oncotarget.com and connect with us on social media:
X
Facebook
YouTube
Instagram
LinkedIn
Pinterest
Spotify, and available wherever you listen to podcasts
Click here to subscribe to Oncotarget publication updates.
For media inquiries, please contact media@impactjournals.com.
Journal
Oncotarget
Method of Research
News article
Subject of Research
Cells
Article Title
PCAIs stimulate MAPK, PI3K/AKT pathways and ROS-Mediated apoptosis in aromatase inhibitor-resistant breast cancer cells while disrupting actin filaments and focal adhesion
Article Publication Date
29-Jul-2025
COI Statement
The authors declare no conflicts of interest. The funders had no role in the design of the study, in the collection of data, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.