Tamoxifen is a candidate first‐in‐class inhibitor of acid ceramidase that reduces amitotic division in polyploid giant cancer cells—Unrecognized players in tumorigenesis

Abstract

Polyploid giant cancer cells (PGCC) represent a poorly understood, small subpopulation of tumor cells that are increasingly being recognized for their critical role in therapy resistance, metastasis, and cancer recurrence. PGCC have the potential to generate progeny through primitive or cleavage-like division, which allows them to evade antimitotic insults. We recently demonstrated that the sphingolipid enzyme acid ceramidase (ASAH1) is required for this process. Since specific ASAH1 inhibitors are not clinically available, we investigated whether tamoxifen, which interferes with ASAH1 function via off-target effects, has a potential clinical benefit independent of estrogen signaling. Our results show that tamoxifen inhibits generation of PGCC offspring in prostate cancer, glioblastoma, and melanoma cells. Analysis of two state-level cancer registries revealed that tamoxifen improves survival outcomes for second, nonbreast cancers that develop in women with early stage breast cancer.Our results suggest that tamoxifen may have a clinical benefit in a variety of cancers that is independent of estrogen signaling and could be due to its inhibition of acid ceramidase. Thus the distinct application of tamoxifen as potentially a first-in-class therapeutic that inhibits the generation of PGCC offspring should be considered in future clinical trials. K E Y W O R D Sacid ceramidase, cancer, PGCC offspring, polyploidy, radiation therapy, recurrence, sphingolipid, tamoxifen

Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

“…Growth of GBM cells in vitro can be inhibited by acid CDase inhibitors such as carmofur [ 77 , 169 ]. Additionally, tamoxifen, a treatment for ER-positive breast cancer, has been shown to inhibit acid CDase and readily crosses the BBB [ 170 ]. As an already approved therapy, this provides potential application for the treatment of GBM.…”

Irradiation‐induced polyploid giant cancer cells are involved in tumor cell repopulation via neosis

“…Polyploid giant cancer cells (PGCCs) are ubiquitous in human cancerous tissues, which contain enlarged or multiple nuclei with increased genomic content when compared to other cancer cells in the same tumor [6][7][8][9].…”

Ceramide Synthase 6 Maximizes p53 Function to Prevent Progeny Formation from Polyploid Giant Cancer Cells

“…We have previously shown that ASAH1 expression increases in PGCC and its activity is critical for PGCC progeny formation across cell lines from different types of cancer [ 13 , 14 ]. To better understand the specific dependence of PGCC on ASAH1, LC/MS analysis was performed to analyze sphingolipid profiles in parental PPC1 cells and their PGCC derivatives in the presence and absence of the ASAH1 inhibitor LCL521.…”

“…We recently identified the sphingolipid enzyme acid ceramidase (ASAH1) as the first molecular target for interfering with the generation of progeny from PGCC [ 13 ]. ASAH1 resides in the lysosome, where it hydrolyzes ceramides to generate sphingosine, which serves as a substrate for sphingosine kinase 1 or 2 (SphK1 and SphK2) that through the addition of a phosphate group generate sphingosine-1-phosphate (S1P) [ 13 , 14 ]. Ceramides and S1P are functionally opposed, with the former generally considered pro-apoptotic and the latter playing roles in survival, mitosis and angiogenesis.…”