Salicylate suppresses the oncogenic hyaluronan network in metastatic breast cancer cells

Abstract

The oncogenic role of hyaluronan in several aspects of tumor biology has been well established. Recent studies by us and others suggest that inhibition of hyaluronan synthesis could represent an emerging therapeutic approach with significant clinical relevance in controlling different breast cancer subtypes, including triple-negative breast cancer. Epidemiological and preclinical studies have revealed the therapeutic potential of aspirin (acetyl salicylate), a classical anti-inflammatory drug, in patients with cancer. However, the underlying molecular mechanisms remain unknown. The present study demonstrates that salicylate, a break down product of aspirin in vivo, alters the organization of hyaluronan matrices by affecting the expression levels of hyaluronan synthesizing (HAS1, 2, 3) and degrading (HYAL-1, -2) enzymes, and that of hyaluronan receptor CD44. In particular, salicylate was found to potently activate AMPK, a kinase known to inhibit HAS2 activity, and caused a dose-dependent decrease of cell associated (intracellular and membrane-bound) as well as secreted hyaluronan, followed by the down-regulation of HAS2 and the induction of HYAL-2 and CD44 in metastatic breast cancer cells. These salicylate-mediated effects were associated with the redistribution of CD44 and actin cytoskeleton that resulted in a less motile cell phenotype. Interestingly, salicylate inhibited metastatic breast cancer cell proliferation and growth by inducing cell growth arrest without signs of apoptosis as evidenced by the substantial decrease of cyclin D1 protein and the absence of cleaved caspase-3, respectively. Collectively, our study offers a possible direction for the development of new matrix-based targeted treatments of metastatic breast cancer subtypes via inhibition of hyaluronan, a pro-angiogenic, pro-inflammatory and tumor promoting glycosaminoglycan.

Cold Atmospheric Plasma Attenuates Breast Cancer Cell Growth Through Regulation of Cell Microenvironment Effectors

“…Low metastatic MCF-7 (ER+) and highly metastatic MDA-MB-231 and Hs 578T (triple negative, ER-/PR-/HER2-) breast cancer cell lines (obtained from the ATCC) were utilized in the present study. For cell cultures, complete media (DMEM, #LM-D1109/500, Biosera) containing 10% fetal bovine serum and antimicrobial agents cocktail were used as described before ( 29 ). All chemicals were of the best commercially available grade.…”

“…To evaluate cell viability, control and DBD-CAP-treated cells were stained with crystal violet solution followed by optical density measurement at 570 nm as described before ( 29 ). As an alternative method, breast cancer cells (control and DBD-CAP-treated cells cultured for 24 h) were detached from the 35-mm dishes with trypsin-EDTA 1× in PBS for 3 min, collected and counted on a hemocytometer counting chamber according to standard protocols.…”

Cell Energy Metabolism and Hyaluronan Synthesis

“…Interestingly, a recent paper reports that the activation of AMPK by salicylate affects the expression levels of HASes as well as the deposition of secreted and cell-associated HA, probably affecting HAS2 phosphorylation or salicylate glucuronidation and therefore, altering the availability of UDP-GlcUA. 97…”

Zinc Complex of 3,5-di-tert-butyl Salicylate Inhibits the Proliferation, Migration, and Invasion of Triple-Negative Breast Cancer Cells

“…Salicylic acids and derivatives are mostly used in antipyretic, analgesic and anti-inflammatory in clinical practice and belong to non-steroidal anti-inflammatory drugs. It also has a certain therapeutic effect on tumors such as breast cancer 7 , pancreatic cancer 8 , lung cancer 9 , ovarian cancer and prostate cancer 10 . It has been found that small doses of aspirin can reduce the risk of multiple cancers, and in vitro aspirin inhibits the growth of various cancer cells including breast cancer through COX-dependent and COX-independent pathway 11 .…”