Piperlongumine, an alkaloid causes inhibition of PI3 K/Akt/mTOR signaling axis to induce caspase-dependent apoptosis in human triple-negative breast cancer cells.

Abstract

The phosphatidylinositol 3-kinase (PI3 K)/Akt/mammalian target of rapamycin (mTOR) signaling axis plays a central role in cell proliferation, growth and survival under physiological conditions. However, aberrant PI3 K/Akt/mTOR signaling has been implicated in many human cancers, including human triple negative breast cancer. Therefore, dual inhibitors of PI3 K/Akt and mTOR signaling could be valuable agents for treating breast cancer. The objective of this study was to investigate the effect of piperlongumine (PPLGM), a natural alkaloid on PI3 K/Akt/mTOR signaling, Akt mediated regulation of NF-kB and apoptosis evasion in human breast cancer cells. Using molecular docking studies, we found that PPLGM physically interacts with the conserved domain of PI3 K and mTOR kinases and the results were comparable with standard dual inhibitor PF04691502. Our results demonstrated that treatment of different human triple-negative breast cancer cells with PPLGM resulted in concentration- and time-dependent growth inhibition. The inhibition of cancer cell growth was associated with G1-phase cell cycle arrest and down-regulation of the NF-kB pathway leads to activation of the mitochondrial apoptotic pathway. It was also found that PPLGM significantly decreased the expression of p-Akt, p70S6K1, 4E-BP1, cyclin D1, Bcl-2, p53 and increased expression of Bax, cytochrome c in human triple-negative breast cancer cells. Although insulin treatment increased the phosphorylation of Akt (Ser473), p70S6K1, 4E-BP1, PPLGM abolished the insulin mediated phosphorylation, it clearly indicates that PPLGM acts through PI3 k/Akt/mTOR axis. Our results suggest that PPLGM may be an effective therapeutic agent for the treatment of human triple negative breast cancer.

• Authors: Shweta Shrivastava, Prasad Kulkarni, Dinesh Thummuri, Manish Kumar Jeengar, V G M Naidu, Mallika Alvala, G Bhanuprakash Redddy, Sistla Ramakrishna
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 19 Issue 7 Pg. 1148-64 (Jul 2014) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 24729100 (Publication Type: Journal Article)

Chemical References

• Alkaloids
• Dioxolanes
• Reactive Oxygen Species
• MTOR protein, human
• Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Caspases
• piperlonguminine

Topics

• Alkaloids (pharmacology)
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Cycle Checkpoints (drug effects, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Fragmentation (drug effects)
• Dioxolanes (pharmacology)
• Female
• Humans
• Molecular Docking Simulation
• Phosphatidylinositol 3-Kinase (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)
• Triple Negative Breast Neoplasms (metabolism, pathology)