The clinical significance of CRABPII has been highlighted in several types of cancer, including non-small lung cancer ( 18), non-myeloma skin cancer ( 19) and pancreatic cancer cells ( 20), pinpointing that restoring the CRABPII signaling pathway may serve as a therapeutic intervention to ameliorate the efficacy of RA or sensitize cancer cells to this hormone. Recent study has demonstrated the importance of CRABPII in mammary carcinoma tumor growth suppression through RA-dependent and RA-independent mechanism ( 17). While decrease in proliferation and cell cycle arrest of cancer cells occurs at an earlier time frame of within 2 days, the apoptotic effects of retinoids begin on day 4 of treatment, with increased apoptosis after day 5 or 6 of treatment ( 15, 16). Retinoids repress genes involved in cell division and cell proliferation, which is followed by differentiation, without affecting cell viability. The differential effects of retinoids on anti-proliferation, cell cycle arrest and apoptosis is dependent on the concentration of RA and the time frame of RA treatment ( 15, 16). Due to the dual and opposing function of RA, the growth inhibitory effects of RA are determined by the expression of the regulatory factors, CRABPII, RARs, FABP5 and PPARβ/δ. On the other hand, fatty acid-binding protein 5 (FABP5) can transport RA to its cognate receptor, PPARβ/δ which targets genes that are involved in proliferation and cell growth ( 10– 13).
Delivery of RA to RARs is facilitated by cellular RA-binding protein II (CRABPII), which sequesters RA, translocates to the nucleus, channels RA to RAR and enhances the transcriptional activity of RAR target genes ( 6, 8, 14). However, binding of RA to the alternative nuclear receptor, peroxisome proliferator-activated receptor β/δ (PPARβ/δ) transduces signals which facilitate cell growth, promote cell survival and protect cells against apoptosis ( 10– 13). The ligand binding domain of the retinoic acid receptor (RAR) which includes RARα, RARβ and RARγ and retinoic X receptors RXRα, RXRβ and RXRγ can interact with RA ( 3, 4) and activate genes that are involved in anti-proliferation, apoptosis, differentiation and cell cycle arrest ( 5– 9). Depending on its interacting partner, RA has distinct biological functions. Based on the notion that retinoic acid (RA) promotes cell differentiation, regulates proliferation and apoptosis, it has been combined with anthracycline-based chemotherapy to successfully treat acute promyelocytic leukemia with a success rate of 80% ( 2).
Despite the toxicity associated with retinoids, it is in general considered to be well tolerated pharmacological agent. Retinoids are structurally related to the hormone of vitamin A with all- trans-retinoic acid (ATRA) being the active metabolite. Due to the lack of markers, it carries poor prognosis and presents an emerging need to understand the biology of this subtype of breast cancer and develop alternative therapeutic options. Among the patients with breast cancer, triple-negative breast cancer (TNBC) accounts for 10–20% of the invasive breast cancer which is defined as estrogen receptor (ER)-negative, progesterone receptor (PR)-negative and human epidermal growth factor receptor 2 (HER2)-negative ( 1). With an estimated 1.7 million cases of breast cancer diagnosed worldwide in 2012, this type of cancer remains the most common in women. These findings provide mechanistic insights into sensitizing TNBC cells to RA-mediated cell death by curcumin-induced upregulation of the CRABPII/RAR pathway. Additionally, silencing CRABPII reverses curcumin sensitization of TNBC cells to the apoptotic inducing effects of RA. Co-treatment of the cells with curcumin and RA results in increased apoptosis as demonstrated by elevated cleavage of poly(ADP-ribose) polymerase and cleaved caspase-9. We provide evidence that curcumin upregulates the expression of CRABPII, RARβ and RARγ in two different TNBC cell lines. The purpose of this study was to investigate the role of curcumin in sensitizing RA-resistant triple-negative breast cancer (TNBC) cells to RA-mediated apoptosis. Delivery of RA to RAR by CRABPII enhances the transcriptional activity of genes involved in cell death and cell cycle arrest. Apoptotic responses of RA are exhibited through the cellular RA-binding protein II (CRABPII)/retinoic acid receptor (RAR) signaling cascade. However, development of retinoid resistance is a critical issue and efforts to understand the retinoid signaling pathway may identify useful biomarkers for future clinical trials.
Due to the anti-proliferative and anti-apoptotic effects of retinoic acid (RA), this hormone has emerged as a target for several diseases, including cancer.