Abstract
Alantolactone (ALT), a sesquiterpene lactone component of Inula helenium, has been reported to exert anticancer activity in various cancers. However, the cellular targets and underlying mechanism of anticancer activity of ALT in various cancers including lung cancer has not been fully defined. In the present study, we found that ALT effectively inhibits proliferation and triggers oxidative stress mediated-apoptosis in A549 lung adenocarcinoma cells by inducing ER stress and mitochondrial dysfunction. This ALT-mediated apoptosis was inhibited by NAC while diamide potentiated it. Moreover, ALT effectively suppressed both constitutive and inducible STAT3 activation, inhibited its translocation into nucleus and decreased its DNA binding activity. Further mechanistic study revealed that ALT abrogated STAT3 activation by promoting STAT3 glutathionylation. ROS scavenger NAC reverted ALT-mediated STAT3 glutathionylation and inhibition of STAT3 phosphorylation. Finally, ALT enhanced chemosensitivity of A549 cells to doxorubicin and reversed doxorubicin resistance in A549/DR cells by inhibiting STAT3 activation and P-glycoprotein expression and increasing intracellular accumulation of doxorubicin. Suppression of STAT3 activation by targeting ROS metabolism with ALT thus discloses a previously unrecognized mechanism underlying the biological activity of ALT. Taken together; ALT induces oxidative stress-dependent apoptosis, inhibits STAT3 activation and augments doxorubicin toxicity in A549 lung cancer cells. These findings provide an in-depth insight into the molecular mechanism of ALT in the treatment of lung cancer.
Highlights
Lung cancer is the most common malignancy and leading cause of cancer-related deaths both in men and women worldwide with approximately 1.4 million deaths annually[1], out of which 0.6 million deaths occur only in China[2]
signal transducer and activator of transcription 3 (STAT3) is activated by phosphorylation at tyrosine 705 (Y705) or serine 727 (S727) and its activation is regulated by multiple pathways including cytokine receptors, receptor tyrosine kinases (RTKs), non-receptor tyrosine kinases, G-protein coupled receptors (GPCRs), Toll like receptors and protein phosphatases[14]
We found that ALT primarily induces oxidative stress resulting in endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and inhibition of STAT3 activation which lead to apoptotic cell death in A549 lung cancer cells
Summary
Lung cancer is the most common malignancy and leading cause of cancer-related deaths both in men and women worldwide with approximately 1.4 million deaths annually[1], out of which 0.6 million deaths occur only in China[2]. As STAT3 is one of the major RTKs’ downstream transcription factors, exploring novel chemotherapeutic agents able to effectively inhibit constitutive as well as inducible activation of STAT3 from multiple stimuli through biochemical modification hold greater potential to reduce cancer mortality. Given the acquired drug resistance, genomic instability and aberrant activation of signaling pathways associated with targeted anticancer drugs developed in the past by exploiting the genetic differences between cancer cells and normal cells, it is necessary to explore alternative novel anticancer strategies that can effectively kill cancer cells. ROS-targeted anticancer drug development strategy holds the promise to set the cancer on the road to ruin as it can be applied more broadly against various human cancers of multiple origins irrespective of their genotype and are less likely to suffer from drug resistance. It is dire need to explore the exact molecular mechanism of ROS based treatment for the future development of highly effective anticancer drugs
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