Document Type
Article
Publication Date
2-28-2019
Publication Title
Cancer Letters
DOI
10.1016/j.canlet.2018.11.022
Abstract
SL-1-39 [1-(4-chloro-3-methylphenyl)-3-(4-nitrophenyl)thiourea] is a new flexible heteroarotinoid (Flex-Het) analog derived from the parental compound, SHetA2, previously shown to inhibit cell growth across multiple cancer types. The current study aims to determine growth inhibitory effects of SL-1-39 across the different subtypes of breast cancer cells and delineate its molecular mechanism. Our results demonstrate that while SL-1-39 blocks cell proliferation of all breast cancer subtypes tested, it has the highest efficacy against HER2+ breast cancer cells. Molecular analyses suggest that SL-1-39 prevents S phase progression of HER2+ breast cancer cells (SKBR3 and MDA-MB-453), which is consistent with reduced expression of key cell-cycle regulators at both the protein and transcriptional levels. SL-1-39 treatment also decreases the protein levels of HER2 and pHER2 as well as its downstream effectors, pMAPK and pAKT. Reduction of HER2 and pHER2 at the protein level is attributed to increased lysosomal degradation of total HER2 levels. This is the first study to show that a flexible heteroarotinoid analog modulates the HER2 signaling pathway through lysosomal degradation, and thus further warrants the development of SL-1-39 as a therapeutic option for HER2+ breast cancer.
Recommended Citation
Zou, H., Sevigny, M. B., Liu, S., Madden, D. T., & Louie, M. C. (2019). Novel flexible heteroarotinoid, SL-1-39, inhibits HER2-positive breast cancer cell proliferation by promoting lysosomal degradation of HER2. Cancer Letters, 443, 157-166. doi:10.1016/j.canlet.2018.11.022
Publisher's Statement
Originally published in Cancer Letters, 443, 157-166. The original material can be found here.
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
