Cannabidiolic acid dampens the expression of cyclooxygenase-2 in MDA-MB-231 breast cancer cells: Possible implication of the peroxisome proliferator-activated receptor β/δ abrogation

Abstract

A growing body of experimental evidence strongly suggests that cannabidiolic acid (CBDA), a major component of the fiber-type cannabis plant, exerts a variety of biological activities. We have reported that CBDA can abrogate cyclooxygenase-2 (COX-2) expression and its enzymatic activity. It is established that aberrant expression of COX-2 correlates with the degree of malignancy in breast cancer. Although the reduction of COX-2 expression by CBDA offers an attractive medicinal application, the molecular mechanisms underlying these effects have not fully been established. It has been reported that COX-2 expression is positively controlled by peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in some cancerous cells, although there is "no" modulatory element for PPARβ/δ on the COX-2 promoter. No previous studies have examined whether an interaction between PPARβ/δ-mediated signaling and COX-2 expression exists in MDA-MB-231 cells. We confirmed, for the first time, that COX-2 expression is positively modulated by PPARβ/δ-mediated signaling in MDA-MB-231 cells. CBDA inhibits PPARβ/δ-mediated transcriptional activation stimulated by the PPARβ/δ-specific agonist, GW501516. Furthermore, the disappearance of cellular actin stress fibers, a hallmark of PPARβ/δ and COX-2 pathway activation, as evoked by the GW501516, was effectively reversed by CBDA. Activator protein-1 (AP-1)-driven transcriptional activity directly involved in the regulation of COX-2 was abrogated by the PPARβ/δ-specific inverse agonists (GSK0660/ST-247). Thus, it is implicated that there is positive interaction between PPARβ/δ and AP-1 in regulation of COX-2. These data support the concept that CBDA is a functional down-regulator of COX-2 through the abrogation of PPARβ/δ-related signaling, at least in part, in MDA-MB-231 cells.

The Therapeutic Potential of the Endocannabinoid System in Age-Related Diseases

“…Interestingly, further in vivo studies have confirmed the antitumoral effect of cannabinoids since encouraging results such as reduction in the rate of growth and size of the tumors were reported [ 321 , 322 ]. The same antiproliferative effects were also reported in breast cancer together with the reduction of cell viability, alteration of signaling pathways and impeding cell cycle and promoting apoptosis [ 325 , 326 , 327 , 328 , 329 , 330 ]. Reduction of both tumoral volume and metastases have been also reported in in vivo studies [ 330 ].…”

“…The same antiproliferative effects were also reported in breast cancer together with the reduction of cell viability, alteration of signaling pathways and impeding cell cycle and promoting apoptosis [ 325 , 326 , 327 , 328 , 329 , 330 ]. Reduction of both tumoral volume and metastases have been also reported in in vivo studies [ 330 ]. Moreover, in a recent paper aiming to evaluate the cancer risk in cannabis users, Clark et al reported that several types of head and neck cancer occur less frequently in this population suggesting that the ECS may represent a promising approach for the management of cancer [ 331 ].…”

4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) Targets Estrogen Receptor β, to Evoke the Resistance of Human Breast Cancer MCF-7 Cells to G-1, an Agonist for G Protein-Coupled Estrogen Receptor 1

“…Transfection and Dual-Luciferase Assay The experiments were performed as described previously, with minor modification. 11,16,17) In brief, 24 h before transfection, MCF-7 cells (5 × 10 4 cells) were seeded onto 24-well plates containing MEMα. The DNA mixtures containing 300 ng of pGL4.49[luc2P/TCF-LEF RE/Hygro] plasmid (Promega, Madison, WI, U.S.A.) and 2 ng of the Renilla luciferase reporter plasmid were transfected using Lipofectamine ® LTX with PLUS reagent (Thermo Fisher Scientific, Waltham, MA, U.S.A.) in 24-well plates.…”

Minor Phytocannabinoids: A Misleading Name but a Promising Opportunity for Biomedical Research

“…Although less active than CBD when assayed in HL60 (promyelocytic leukemia) and in CEM (promyelocytic leukemia) cells, remarkable activity was observed against MDA-MB-231 cells, a highly aggressive line of triple-negative breast cancer cells [ 37 ]. The activity was related to the attenuation of the transcriptional activity of PPARβ/δ, both expressed in MDA-MB-23 cells [ 38 ] and of AP-1 [ 39 ]. A cannabis extract rich in CBGA showed cytotoxic activity against colon cancer and human leukemia cells.…”