Abstract
BackgroundThe non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. In NSCLC, the oncogenic AKT-mTOR, ERK and STAT3 pathways are commonly dysregulated and have emerged as attractive targets for therapeutic developments. In a relatively limited subset of NSCLC, these pathways driven by mutant EGFR can be treated by the tyrosine kinase inhibitors (TKIs)-mediated targeted therapy. However, for the most NSCLC, more novel targeted agents are imperatively needed. Therefore, we investigated the inhibitory effects of the active fraction HS7 from Taiwanofungus camphoratus, a unique medicinal fungus in Taiwan, on these pathways in CL1-0 EGFR wild-type human NSCLC cells.MethodsThe active fraction HS7 was prepared by n-hexane extraction of T. camphoratus followed by silica gel chromatography. Its effects on the cell viabilities were determined by sulforhodamine B colorimetric assay. Flow cytometry was used to analyze cell-cycle regulation and apoptosis induction. The changes in cellular protein levels were examined by Western blot.ResultsThe active fraction HS7 vigorously inhibits AKT-mTOR, ERK and STAT3 signaling pathways in CL1-0 cells. At dose of 25 μg/mL, these signaling pathways were almost completely inhibited by HS7, accompanied with induction of cyclin-dependent kinase inhibitors such as p15, p21 and p27. Accordingly, the AKT-mTOR downstream targets p-p70S6K and HIF-1α were also suppressed as well. At this dose, the cell proliferation was profoundly suppressed to 23.4% of control and apoptosis induction was observed.ConclusionsThe active fraction HS7 from n-hexane extract of T. camphoratus exerts multi-targeting activity on the suppression of AKT-mTOR, ERK and STAT3 pathways and induction of p15, p21 and p27 in EGFR wild-type NSCLC cells. This multi-targeting activity of HS7 suggests its potential as an alternative medicine for the treatment of EGFR TKIs resistant NSCLC.
Highlights
The non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide
The active fraction HS7 from n-hexane extract of T. camphoratus exerts multi-targeting activity on the suppression of AKT-mam‐ malian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) pathways and induction of p15, p21 and p27 in epidermal growth factor receptor (EGFR) wild-type NSCLC cells. This multi-targeting activity of HS7 suggests its potential as an alternative medicine for the treatment of EGFR tyrosine kinase inhibitor (TKI) resistant NSCLC
We explore its effects on the aforementioned AKT-mTOR, ERK and STAT3 signaling pathways in a human NSCLC cell line CL1-0, which harbors wild-type EGFR and is resistant to EGFR TKIs [19]
Summary
The non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. It has been reported that 50–70% overexpression of phosphorylated AKT [4], 70% expression of activated ERK [5] and over 50% high levels of activated STAT3 [6] were observed in NSCLC Aberrant activation of these three signaling pathways results in uncontrolled proliferation, apoptosis resistance and other oncogenic cascades in lung cancer cells [4, 6,7,8]. There has been increasing research interest in identifying novel therapeutics to target these oncogenic signaling pathways for effectively treating NSCLC patients [4, 9, 10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
