Effects of gossypol on apoptosis-related gene expression in racially distinct triple-negative breast cancer cells

Apoptosis is a gene-directed mechanism that regulates cell proliferation and maintains homeostasis. Moreover, an aberrant apoptotic process can lead to several pathological conditions, such as tumorigenesis and cancer metastasis. In the present study, the apoptotic effect of the natural polyphenol compound gossypol (GOSS) was investigated in triple-negative breast cancer (TNBC) cells. The effect of GOSS was evaluated in two cell lines representative of a Caucasian-American and African-American origin, MDA-MB-231 (MM-231) and MDA-MB-468 (MM-468), respectively. A similar response to both cytotoxicity and proliferation was observed in the two cell lines. However, MM-468 cells were 2-fold more sensitive to the apoptotic effect of the compound, which was accompanied by a longer delay in colony formation. Furthermore, GOSS was found to alter the mRNA expression of many apoptosis-related genes. The compound significantly upregulated growth arrest and DNA damage-inducible 45 alpha protein (GADD45A), tumor necrosis factor receptor superfamily 9 (TNFRSF9) and BCL2 interacting protein 3 (BNIP3) in MM-231 cells. Similarly, GADD45A and BNIP3 were upregulated in MM-468 cells. A significant finding in this study is the profound 159-fold increase in TNF gene expression that was observed in MM-468 cells. Moreover, the apoptosis-suppressor gene baculoviral IAP repeat containing 5 (BIRC5) was significantly repressed (by more than 90%) in both cell lines, as well as death-associated protein kinase 1 (DAPK1) in MM-231 cells and tumor protein 73 (TP73) in MM-468 cells. In conclusion, the data obtained in this study provide a molecular understanding of the GOSS-induced apoptosis effect and suggest the importance of this polyphenol compound targeted towards TNBC treatment, particularly in African-American women.