Abstract
A number of studies have shown that apoptosis resistance can be observed in multiple human tumors; however the detailed mechanism remains unclear. In the present study, we demonstrated that the abnormal overexpression of the C terminus of Hsc70-interacting protein (CHIP) induced apoptosis resistance by regulating the AKT/FoxO/Bim signaling pathway in the breast cancer cell MCF7 and the human non-tumorigenic cell MCF10A. We found that CHIP overexpression in MCF7 and MCF10A cells activated AKT and inhibited the Forkhead box O (FoxO) transcription factors FoxO1, FoxO3, and FoxO4, thereby inhibiting transcription of the target genes bim and pten. Inhibition of PI3K by a chemical reagent revealed that these events may be critical for CHIP-induced apoptosis resistance. We also determined that inhibition of FoxO3 by CHIP led to the decrease in PTEN and further activated the AKT survival pathway. We corroborated our findings in breast cancer tissues. In general, the CHIP-modulated AKT/FoxO/Bim signaling pathway was shown to induce apoptosis resistance by decreasing the protein level of the tumor suppressor PTEN in both transcriptional and post-translational regulations.
Highlights
PI3K/AKT signaling has been identified to be deregulated with high frequency in human tumors, especially in breast cancer
We found that C terminus of Hsc70-interacting protein (CHIP) overexpression promoted PI3K/AKT survival pathway activation in both MCF7 and MCF-10A cells (Figure 1A)
Our study demonstrated that CHIP-induced apoptosis resistance is closely associated with the AKT/FoxO3/Bim signaling pathway in both normal breast epithelial cell MCF10A and breast cancer cell MCF7 cells
Summary
PI3K/AKT signaling has been identified to be deregulated with high frequency in human tumors, especially in breast cancer. Abnormal activated PI3K/AKT signaling can lead to excessive proliferation and resistance to chemotherapy-induced apoptosis. Excessive PI3K/AKT signaling that leads to cell proliferation and defense against apoptosis occurs frequently in breast cancer. Forkhead box O (FoxO) transcription factors are identified as the essential regulators of multiple cellular activities such as proliferation, defense against oxidative stress, and apoptosis [1,2]. These factors are associated with various human cancers [3,4]. As FoxO protein is reduced, the target genes involved in apoptosis, such as puma and bim, become inhibited in transcriptional steps [6,7,8]
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