Zinc enhances CDKN2A, pRb1 expression and regulates functional apoptosis via upregulation of p53 and p21 expression in human breast cancer MCF-7 cell

• Zinc deficiency cause oxidative stress and DNA damage to MCF-7 cells.
• Zinc deficiency causes increased breast cancer MCF-7 cell proliferation.
• In zinc depleted cells, we found decreased expression of CDKN2A, pRb1 and p53 genes.
• IC50 (15 μM) level of Zinc, enhance CDKN2A, pRb1, p53 and down regulate mdm2.
• Zinc inhibits breast cancer cell proliferation via regulation of tumor suppressor gene.

Zinc (Zn) is an essential trace elements, its deficiency is associated with increased incidence of human breast cancer. We aimed to study the effect of Zn on human breast cancer MCF-7 cells cultured in Zn depleted and Zn adequate medium. We found increased cancer cell growth in zinc depleted condition, further Zn supplementation inhibits the viability of breast cancer MCF-7 cell cultured in Zn deficient condition and the IC25, IC50 value for Zn is 6.2 μM, 15 μM, respectively after 48 h. Zn markedly induced apoptosis through the characteristic apoptotic morphological changes and DNA fragmentation after 48 h. In addition, Zn deficient cells significantly triggered intracellular ROS level and develop oxidative stress induced DNA damage; it was confirmed by elevated expression of CYP1A, GPX, GSK3β and TNF-α gene. Zinc depleted MCF-7 cells expressed significantly (p ≤ 0.001) decreased levels of CDKN2A, pRb1, p53 and increased the level of mdm2 expression. Zn supplementation (IC50 = 15 μM), increased significantly CDKN2A, pRB1 & p53 and markedly reduced mdm2 expression; also protein expression levels of CDKN2A and pRb1 was significantly increased. In addition, intrinsic apoptotic pathway related genes such as Bax, caspase-3, 8, 9 & p21 expression was enhanced and finally induced cell apoptosis. In conclusion, physiological level of zinc is important to prevent DNA damage and MCF-7 cell proliferation via regulation of tumor suppressor gene.