Bag-1L is a Stress-withstand Molecule Prevents the Downregulation of Mcl-1 and c-Raf Under Control of Heat Shock Proteins in Cisplatin Treated HeLa Cervix Cancer Cells

Abstract

Background: Cisplatin, a DNA damaging agent, induces apoptosis through increasing DNA fragmentation. However, identification of intrinsic resistance molecules against Cisplatin is vital to estimate the success of therapy. Bag-1 (Bcl-2-associated anthanogene) is one anti-apoptotic protein involved in drug resistance impacting on therapeutic efficiency. Elevated levels of this protein are related with increase cell proliferation rates, motility and also cancer development. For this reason, we aimed to understand the role of Bag-1 expression in Cisplatininduced apoptosis in HeLa cervix cancer cells. Cisplatin decreased cell viability in time-and dose-dependent manner in wt and Bag-1L+HeLa cells. Although, 10μM Cisplatin treatment induced cell death within 24h by activating caspases in wt cells, Bag-1L stable transfection protected cells against Cisplatin treatment. To assess the potential protective role of Bag-1, we first checked the expression profile of interacting anti-apoptotic partners of Bag-1. We found that forced Bag-1L expression prevented Cisplatin-induced apoptosis through acting on Mcl-1 expression, which was reduced after Cisplatin treatment in wt HeLa cells. This mechanism was also supported by the regulation of heat shock protein (Hsp) family members, Hsp90 and Hsp40, which were involved in the regulation Bag-1 interactome including several anti-apoptotic Bcl-2 family members and c-Raf.

Molecular mechanisms of cisplatin resistance in cervical cancer

“… 45 Similarly, overexpression of Bag-1L prevents cisplatin-induced apoptosis by affecting Raf/Ras signaling and the expression of Mcl-1 and heat-shock proteins (HSPs) in HeLa cells. 49 Furthermore, stable overexpression of Bag-1 p romotes resistance to cisplatin-induced apoptosis in C33A cells. 47 In addition to the upregulation of anti-apoptotic proteins, suppression of proapoptotic effector proteins also contributes to the development of CPR.…”

Synergism of ursolic acid and cisplatin promotes apoptosis and enhances growth inhibition of cervical cancer cells via suppressing NF-κB p65

“…Cisplatin (DDP) is a cell cycle non-specific antineoplastic drug, which is applicable for the treatment of several types of cancers and it is also recommended to applied to chemotherapy for epithelial malignancies, such as lung cancer [ 14 ], ovarian cancer [ 15 ], testicular cancer [ 16 ] and cervical cancer [ 17 ]. DDP and its derivatives have been found to have encouraging anti-cancer effects on different types of cancers [ 18 ].…”

Therapeutic Potency of Nanoformulations of siRNAs and shRNAs in Animal Models of Cancers

“…It regulates Bcl-2 gene expression and mimics the anti-apoptotic activities via bridging between the growth factor and anti-apoptotic mechanism. The aberrant expression of Bag-1 has been found in breast, lung, cervix, esophagus and colorectal cancers [ 354 , 355 , 356 ]. Colorectal cancer has the second largest morbidity and mortality rate all over the world [ 357 , 358 ] and human Bcl-2 associated athanogene-1(bag-1) anti-apoptotic gene is found to be involved in the tumor genesis of colorectal cancer (CRC) by mediating progression and metastasis and acts as a positive regulator of Bcl-2 gene in CRC [ 359 ].…”