Curcumin Sensitizes 4T1 Murine Breast Cancer Cells to Cisplatin Through PAR4 Secretion

Abstract

Background/Aim: Prostate apoptosis response 4 (PAR4), a tumour-suppressor protein, selectively induces apoptosis of cancer cells without affecting normal cells. Its soluble form is induced by secretagogues (e.g., chloroquine), and it induces apoptosis by interacting with the receptor of glucose-regulated protein 78, which is overexpressed in cancer cells. In this study, curcumin was analyzed as an inducer of PAR4 expression in 4T1 murine breast cancer cell. and its ability to induce PAR4 secretion in Balb/c mice. In addition, the cisplatin sensitizing effect of soluble PAR4 was analyzed. Material and Methods: The 4T1 cell line was treated in vitro using different concentrations of curcumin; cell viability was analyzed using 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay and PAR4 expression by western blotting. The expression of soluble PAR4 in the serum of mice treated with intraperitoneal curcumin was analyzed using the dot-blot method. Moreover, MTT assay was used to analyze the effects of serum from curcumin-treated mice on cell viability. Tumor size was analyzed in mice treated with curcumin alone and in combination with cisplatin. Results: Curcumin showed a dose-and time-dependent effects on cell viability on 4T1 cells, as well as increasing PAR4 expression. Compared with the control group (phosphate-buffered saline), mice treated with curcumin showed an increase in plasma PAR4. In the Balb/C tumor model, mice treated with curcumin and cisplatin showed greater tumor shrinkage than the control group. Conclusion: These results indicate that curcumin induces expression of soluble PAR4 and sensitizes tumor cells to cisplatin.Prostate apoptosis response 4 (PAR4) is a tumor-suppressor gene that induces apoptosis via extracellular and intracellular mechanisms in cancer cells without affecting normal cells (1, 2). Its expression is decreased in some neoplasms, and it is associated with a poor prognosis (3, 4). In breast cancer, metastasis, resistance, and recurrence require PAR4 dysregulation (5-7). Recently, PAR4 has been observed to be secreted spontaneously in normal cell culture and not in cancer cells by various agents that induce endoplasmic reticulum stress in both mice and humans; this increases cellular secretion of PAR4 via a P53-dependent mechanism (5,8,9). Chloroquine and hydroxychloroquine are antimalarial drugs that act as robust secretagogues of PAR4 (5). On the other hand, arylquinoline 1 disrupts the integration between PAR4-vimentin, increasing its secretion (9, 10). Through the extracellular interaction with glucoseregulated protein 78 (GRP78), which is overexpressed on the surface of cancer cells and is correlated with malignancy, soluble PAR4 causes extrinsic apoptosis via FAS-associated death domain/caspase 8 and caspase 3 pathways in various 2767

An Overview of the Enhanced Effects of Curcumin and Chemotherapeutic Agents in Combined Cancer Treatments

“…Recently, an in vivo study showed that treatment with curcumin followed by cisplatin resulted in complete regression of tumour mass in induced breast cancer. In addition, curcumin had a positive effect on the expression of Par4 , a tumour suppressor gene whose decreased expression is associated with poor prognosis [ 73 ].…”

Papel de Par-4 en tumores de cáncer de mama en etapas tardías y recurrentes

“…La sobreexpresión de Par-4 combinada con CDDP ejerce un efecto sinérgico en líneas celulares y suprime el crecimiento del xenoinjerto en ratones desnudos (60). La curcumina incrementa la expresión de Par-4 y sensibiliza la línea celular de cáncer de mama murino 4T1 al CDDP (61). Por otra parte, Tan y col. observaron que la regulación negativa de Par-4 confiere resistencia a CDDP a través de la EMT dependiente de la vía fosfatidilinositol-3-kinasa (PI3K/Akt) en la línea celular primaria de tumor pancreático humano (BXPC-3); por lo tanto, Par-4 puede ser un objetivo potencial para superar la resistencia a CDDP en el cáncer de páncreas.…”

A Docking and Network Pharmacology Study on the Molecular Mechanisms of Curcumin in Dental Caries and Streptococcus mutans

“…Curcuma longa L. has many active compounds, the most important of which is curcumin. Several studies have shown that curcumin benefits different diseases [ 8 , 9 , 10 ]. Some studies revealed that curcumin could potentially prevent and be essential in treating dental caries as a natural, accessible, safe, and inexpensive agent to increase oral and dental health [ 11 ].…”