A mitophagy-mediated autophagy pathway that triggers apoptotic cell
death in non-small cell lung cancer (NSCLC) for anticancer chemotherapy
by Norcantharidin
Abstract
Norcantharidin (NCTD) is a traditional Chinese medicine (TCM) that has
been used for over 2000 years to treat many diseases. It can inhibit
proliferation and induce apoptosis in multiple types of cancer cells.
However, the anticancer activities of NCTD in non-small cell lung cancer
(NSCLC) cells, and its underlying mechanisms, have not been
investigated. In this study, NCTD suppressed the growth and
proliferation of A549 non-small cell lung cancer cells in a
dose-dependent manner, apparently by reducing the mitochondrial membrane
potential and inducing G2/M phase arrest. NCTD induced apoptosis by
increasing the ratio of Bax/Bcl-2 and Bax/Mcl-1 and activating
caspase-3/9-dependent mitochondrial pathways. Treatment with NCTD
induced significant mitophagy and autophagy, as the demonstrated by
accumulation of punctate LC3 in the cytoplasm and the characteristic
clustering of the mitochondria around the nucleus, increasing the
conversion of LC3-I to LC3-II and reducing the protein expression of
p62. In addition, we also observed an increase in p-AMPK, p-JNK and
p-c-jun and decrease in p-AKT and mTOR. In conclusion, our results
demonstrate that NCTD can reduce the mitochondrial membrane potential
and subsequently increase cellular autophagy and apoptosis; the
AMPK/mTOR/ULK1, JNK and Akt/mTOR signaling pathways were involved in
these processes. Thus, the traditional Chinese medicine NCTD could be a
novel therapeutic for treating NSCLC cells.