Abstract
Lung cancer is the most common and lethal malignant disease for which the development of efficacious chemotherapeutic agents remains an urgent need. Pristimerin (PRIS), a natural bioactive component isolated from various plant species in the Celastraceae and Hippocrateaceae families, has been reported to exhibit outstanding antitumor effects in several types of cells. However, the underlying mechanisms involved remain poorly understood. Here, we reported the novel finding that PRIS significantly suppressed lung cancer growth in conditionally reprogrammed patient-derived lung adenocarcinoma cells (CRLCs). We demonstrated that PRIS inhibited the cell viabilities, migrative and invaded abilities, and capillary structure formation of CRLCs. Furthermore, our results clarified that PRIS induced mitochondrial dysfunction through reactive oxygen species (ROS) generation, activation of caspase-9, caspase-3, and caspase-4, and expression of endoplasmic reticulum (ER) stress-associated proteins. Inhibition of ER stress by 4-PBA (4-phenylbutyric acid, a specific ER stress inhibitor) or CHOP siRNA transfection ameliorated PRIS-induced loss of mitochondrial membrane potential and intrinsic apoptosis. The present study also provides mechanistic evidence that PRIS suppressed the EphB4/CDC42/N-WASP signaling pathway, which is required for mitochondrial-mediated intrinsic apoptosis, activation of ER stress, and stimulation of caspase-4 induced by PRIS, and consequently resulting in suppressed cell viability, migration, and angiogenesis in CRLCs. Taken together, by providing a mechanistic insight into the modulation of ER stress-induced cell death in CRLCs by PRIS, we suggest that PRIS has a strong potential of being a new antitumor therapeutic agent with applications in the fields of human lung adenocarcinoma.
Highlights
As the leading cause of cancer mortality with the most common incidence, lung cancer is still therapeutically challenged all over the world [1]
In an effort to confirm the possible role of N-WASP in the promotion of endoplasmic reticulum (ER) stress, we showed that Small Interfering RNA (siRNA) transfection of N-WASP upregulated the expression of CHOP, GRP78, and ATF4, promoted cleaved caspase-4 and caspase-3 activation, elevated the Bax/Bcl-2 ratio expression, and increased significant reactive oxygen species (ROS) production (Figures 8(f)–8(i))
The results demonstrated that inhibition of ER stress by pharmacological and molecular means prevented PRIS-induced ROS production and membrane potential (MMP) decline and reduced PRIS-induced apoptotic cell death, which suggests that ER stress concurrently plays a role in mitochondrial dysfunction in PRIS-treated conditionally reprogrammed patient-derived lung adenocarcinoma cells (CRLCs)
Summary
As the leading cause of cancer mortality with the most common incidence, lung cancer is still therapeutically challenged all over the world [1]. In the past three decades, strategies based on the combination of surgery and chemotherapy regimens have been developed in an initial treatment of lung cancer. The overall survival rate for lung cancer has not significantly improved because these tumors have a high incidence of recurrence and commonly lead to death. PRIS was showed to inhibit tumor growth of various human cancers such as colon [5], prostate [6], pancreatic [7], cervical [8], and multiple myeloma tumors [9]. Reactive oxygen species (ROS) generation, and endoplasmic reticulum (ER) stress have been implicated in PRIS-induced cell death, the molecular pathways underlying the anticancer effect of PRIS are dependent on the cellular contexts and remain to be further investigated [9,10,11]
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