Docosahexaenoic Acid Reverted the All-trans Retinoic Acid-Induced Cellular Proliferation of T24 Bladder Cancer Cell Line

Abstract

The treatment of solid cancers with pharmacological all-trans retinoic acid (ATRA) concentrations, even if it is a gold standard therapy for the acute promyelocytic leukaemia (APL), is not always effective due to some resistance mechanisms. Here the resistance to ATRA treatment of T24 cell line, bladder cancer, was investigated. T24 was not only resistant to cell death when treated at concentrations up to 20 µM of ATRA, but it was also able to stimulate the cellular proliferation. An over-expression of the fatty acid binding protein 5 (FABP5) in conjunction with the cellular retinol-binding protein-II (CRABP-II) down-expression was found. However, the direct inhibition of the peroxisome proliferator-activated receptor β/δ (PPARβ/δ) did not abolish T24 proliferation, but rather potentiated it. Moreover, considering the ability of the long-chain fatty acids (LCFAs) to displace ATRA from FABP5, the actions of the saturated palmitic acid (PA), unsaturated omega-6 linoleic acid (LA) and omega-3 docosahexaenoic acid (DHA) were evaluated to counteract ATRA-related proliferation. ATRA-PA co-treatment induces cellular growth inhibition, while ATRA-LA co-treatment induces cellular growth enhancement. However, even if DHA is unsaturated LCFA as LA, it was able to reverse the ATRA-induced cellular proliferation of T24, bringing the viability percentages at the levels of the control.

m6A-induced lncDBET promotes the malignant progression of bladder cancer through FABP5-mediated lipid metabolism

“…Enrichment of proteins by lncDBET between lncDBET probe-treated cells and control probe-treated cells was presented, and 8 candidates (HRNR, POF1B, ALOX12B, FABP5, FLG, SBSN, PRDX2, HAL) were identified as potential lncDBET targets (|FC| ≥ 2, P < 0.05) (Figure 5 B). Taking FC and binding score ( Table S5 ), KEGG pathway analysis (Figure 5 C) and association with human cancers into account as screening standards 26 , only the PPAR signaling pathway was related to BCa, and thus, only FABP5 was selected for further verification. In addition, the peptide sequence of FABP5 “LVVECVMNNVTCTR” was identified (Figure 5 D).…”

The Effect of Retinoic Acid on Arsenite-Transformed Malignant UROtsa Bladder Cancer Cells: In Vitro Model of Basal Muscle-Invasive Bladder Cancer

“…The role of retinoic acid in bladder cancers remains under investigation. In vitro studies show variable effects of retinoids in different bladder cancer cells [ 19 , 21 , 22 ], with no studies dedicated to the effects of retinoids on a specific molecular subtype of bladder cancer, including basal muscle-invasive bladder cancer. The effect of retinoids needs to be investigated in each subtype of bladder cancer to determine if there is an avenue for precision therapy in bladder cancer.…”

“…Retinoic acid (all-trans retinoic acid (ATRA), tretinoin) is an active metabolite of vitamin A that can modify both the retinoic acid receptor (RAR) and the retinoid X receptor (RXR) [ 18 ]. In vitro studies have shown variable effects of retinoids on bladder cancer cell lines (T24, RT4, 5637, RT112, and HT-1376 cells), ranging from a cytostatic effect, stimulation of proliferation, and inhibition of EGF-stimulated cell proliferation to direct activation of PPARγ [ 19 , 20 , 21 , 22 ]. In vivo studies have been limited, primarily focusing on the effect of dietary vitamin A in preventing bladder cancer development [ 16 ], with scarce data available on the effect of retinoids on bladder cancer xenografts in animal models.…”

Vitamin A and Retinoids in Bladder Cancer Chemoprevention and Treatment: A Narrative Review of Current Evidence, Challenges and Future Prospects

“…Different retinoids induced the expression of different nuclear retinoid receptors ( RARα , RARβ , RARγ ) and differentially altered the expression of apoptosis-associated genes ( p53 , GADD45 , bcl-2 , casp3 ) [ 74 , 88 ]. Moreover, it was shown that ATRA treatment was not always effective due to some resistance mechanisms and that ATRA could even induce a dose- and time-dependent cell proliferation [ 86 ]. A similar effect was also shown for bexarotene (also known as LGD1069 or Ro 26-445, brand name Targretin), which increased the incidence and size of tumours that developed in the BBN model [ 90 ].…”

“…The pharmacological use of retinoids encounters several limitations, such as the low concentrations of retinoids at the tumour site, short half-life, poor water solubility, susceptibility to light, heat, and oxidants, and rapid degradation during digestion resulting in low bioavailability and bioaccessibility [ 20 , 86 ]. One of the ways to increase retinoid plasma levels is to combine retinoid treatment with agents that inhibit retinoid degradation, which was tested in a BC clinical trial.…”