Thymosin alpha 1 suppresses proliferation and induces apoptosis in breast cancer cells through PTEN-mediated inhibition of PI3K/Akt/mTOR signaling pathway

Abstract

Thymosin alpha 1 (Tα1), an immunoactive peptide, has been shown to inhibit cell proliferation and induce apoptosis in human leukemia, non-small cell lung cancer, melanoma, and other human cancers. However, the response and molecular mechanism of breast cancer cells exposed to Tα1 remain unclear. PTEN, a tumor suppressor gene, is frequently mutated in a variety of human cancers. In the present study, we aimed to investigate the biological roles of PTEN in the growth inhibition of human breast cancer cells exposed to Tα1. Using wild-type and mutant PTEN-expressing cells, we found a strong correlation between PTEN status and Tα1-mediated growth inhibition of breast cancer cells. The growth inhibition effect was more pronounced in breast cancer cells in which Tα1 enhanced PTEN expression, whereas endogenous PTEN knockdown reversed the growth inhibition effect of Tα1 in breast cancer cells. Further investigation revealed that PTEN up-regulation, which was induced by Tα1, can inhibit the activation of the PI3K/Akt/mTOR signaling pathway, leading to the growth inhibition of breast cancer cells. The addition of the synergy between Tα1 and the inhibition of PI3K/Akt/mTOR activation could strongly block cell viability in PTEN down-regulated breast cancer cells. PTEN-overexpressing cells not only up-regulated Bax and cleaved caspase-3/9 and PARP expression but also down-regulated Bcl-2 compared to the treatment with Tα1 alone. Together these findings suggest that PTEN mediates Tα1-induced apoptosis through the mitochondrial death cascade and inhibition of the PI3K/Akt/mTOR signaling pathway in breast cancer cells.

Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia

“…At the same time, the number of apoptotic cells increased by 22-fold ( Figure 4B). These results are in agreement with the findings of other authors (46,47).…”

“…We then evaluated the effect of chronic treatment with Tα-1 on the proliferation and apoptosis of MCF-7 breast cancer cells. Indeed, various research groups reported that long-term treatment (72 hours) with Tα-1 (in the 150-500 μM concentration range) decreases the proliferation rate of MCF-7 and causes cell apoptosis (46,47). Therefore, we plated MCF-7 at low density on 96-well plates suitable for confocal high-content imaging and evaluated cell proliferation for 72 hours following treatment with Tα-1 (100 ng/ml) or scrambled peptide (100 ng/ml).…”

LncRNA TP73-AS1 Promotes Cell Proliferation and Inhibits Cell Apoptosis in Clear Cell Renal Cell Carcinoma Through Repressing KISS1 Expression and Inactivation of PI3K/Akt/mTOR Signaling Pathway

“…But, differently, we identified that mTOR signaling, may be served as another way that mediated the role of KISS1 in cell function in ccRCC cells. Activation of the PI3K/Akt/mTOR pathway protects various cell types from apoptosis that is induced by the withdrawal of survival factors [39,40]. We found that knockdown of TP73-AS1 significantly activated mTOR signaling, whereas overexpression of TP73-AS1 induced inhibition of mTOR pathway while overexpressed KISS1 partly abolished this inhibition effects.…”

Mechanism of immune evasion in breast cancer

“…The control and reduction of apoptosis, the highly selective and programmed form of cell death, have been considered a fundamental strategy for evading the immune response in cancer development 26. Any part of the apoptosis pathway can be disturbed, causing endless proliferation of almost all types of cancers, including BC 27.…”