Bag‐1 promotes cell survival through c‐Myc‐mediated ODC upregulation that is not preferred under apoptotic stimuli in MCF‐7 cells

Abstract

Bag-1, Bcl-2 associated athanogene-1, is a multifunctional protein that can regulate a wide variety of cellular processes: proliferation, cell survival, transcription, apoptosis and motility. Bag-1 interacts with various targets in the modulation of these pathways; yet molecular details of Bag-1's involvement in each cellular event are still unclear. We first showed that forced Bag-1 expression promotes cell survival and prevents drug-induced apoptosis in MCF-7 breast cancer cells. Increased mRNA expressions of c-myc protooncogene and ornithine decarboxylase (ODC), biosynthetic enzyme of polyamines, were detected in Bag-1L+ cells, and western blots against the protein product of c-Myc and ODC confirmed these findings. Once ODC, a c-Myc target, gets activated, polyamine biosynthesis increases. We observed enhanced polyamine content in the Bag-1L+ cells. On the contrary, when polyamine catabolic mechanisms were investigated, Bag-1 silencing suppressed biosynthesis of polyamines because of the downregulation of ODC and upregulation of PAO. Exposure of cells to apoptotic inducers enhances the cell death mechanism by producing toxic products such as H2 O2 and aldehydes. Bag-1L+ cells prevented drug-induced PAO activation leading to a decrease in H2 O2 production following cisplatin or paclitaxel treatment. In this line, our results suggested that Bag-1 indirectly affects cell survival through c-Myc activated signalling that causes elevation of ODC levels, leading to an increase of the polyamine content.

Bag-1 stimulates Bad phosphorylation through activation of Akt and Raf kinases to mediate cell survival in breast cancer

“…Despite these differences, Bag-1 overexpression was a common feature in all breast cancer subtypes. In accordance with this finding, ectopic expression of Bag-1 increased proliferation, whereas its silencing increased apoptotic cell death in all cell lines tested independent of their receptor and tumorigenicity status [7, 31–33].…”

“…Through these interactions, Bag-1 is involved in the regulation of diverse cellular processes such as apoptosis, proteostasis, transcription and motility [5]. Bag-1 protects cells from a variety of apoptotic signals [2, 6], and plays important roles in breast cancer development and chemoresistance [7].…”

Polyamine metabolism and cancer: treatments, challenges and opportunities

“…Thus, the MYC signalling pathway is seen as one of the major drivers in dysregulated polyamine metabolism-associated cancers. As members of the MYC family are frequently amplified or overexpressed in cancer, the regulation of polyamine biosynthesis by MYC family genes plays a substantial role in multiple cancer types including leukaemias and lung, neural and breast cancers 33–37 . Furthermore, the link between MYC, hypusine formation and eIF5A activation likely plays a role in neoplastic transformation 9 (FIG.…”

Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat

“… 75 This MYC-mediated regulation of polyamine biosynthesis has been confirmed in multiple cancers, such as leukemias, lung carcinomas, neuroblastomas, and breast cancers. 76 – 79 Recent studies revealed that mTORC1 stabilizes pro-S-adenosyl methionine (AdoMet) decarboxylase (pro-AdoMetDC), leading to increased AdoMetDC to further promote polyamine biosynthesis in prostate cancer. MYC has been linked to mTORC1 activation by increasing nutrient import.…”