Cantharidin Induced Oral Squamous Cell Carcinoma Cell Apoptosis via the JNK-Regulated Mitochondria and Endoplasmic Reticulum Stress-Related Signaling Pathways

Abstract

Oral cancer is a subtype of head and neck cancer which represents 2.65% of all human malignancies. Most of oral cancer is histopathologically diagnosed as oral squamous cell carcinoma (OSCC). OSCC is characterized by a high degree of local invasion and a high rate of metastasis to the cervical lymph nodes. How to prevention and treatment of OSCC is important and imperative. Here, we investigated the therapeutic effect and molecular mechanism of cantharidin, an active compound isolated from blister beetles, on OSCC in vitro. Results showed that cantharidin significantly decreased cell viability in human tongue squamous carcinoma-derived SAS, CAL-27, and SCC-4 cell lines. The further mechanistic studies were carried out in SAS cells. Cantharidin also significantly increased apoptosis-related signals, including caspase-9, caspase-7 and caspase-3 proteins. Besides, cantharidin decreased mitochondrial transmembrane potential (MMP) and induced cytochrome c and apoptosis inducing factor (AIF) release. Cantharidin also increased Bax, Bid, and Bak protein expressions and decreased Bcl-2 protein expression. Cantharidin could also increase the endoplasmic reticulum (ER) stress signals, including the expressions of phosphorylated eIF-2α and CHOP, but not Grp78 and Grp94. Furthermore, cantharidin reduced pro-caspase-12 protein expression. In signals of mitogen-activated protein kinases, cantharidin increased the phosphorylation of JNK, but not ERK and p38. Transfection of shRNA-JNK to OSCC cells effectively reversed the cantharidin-induced cell apoptotic signals, including the mitochondrial and ER stress-related signaling molecules. Taken together, these findings suggest that cantharidin induces apoptosis in OSCC cells via the JNK-regulated mitochondria and ER stress-related signaling pathways.

Cantharidin suppresses cell growth and migration, and activates autophagy in human non-small cell lung cancer cells

“…Previous studies have reported that CTD efficiently inhibited proliferation and induced apoptosis in various cancer cells, including oral squamous cell carcinoma, renal carcinoma and gastric cancer cells (18)(19)(20). The results of the present study also demonstrated that CTD inhibited A549 cell proliferation and migration, which is consistent with the results of previous studies (18)(19)(20).…”

“…The results of the present study also demonstrated that CTD inhibited A549 cell proliferation and migration, which is consistent with the results of previous studies (18)(19)(20). The combined results of these studies provide evidence that CTD is a promising therapeutic candidate for the treatment of NSCLC.…”

Cantharidin alters GPI-anchored protein sorting by targeting Cdc1 mediated remodeling in Endoplasmic Reticulum

“…We found 1 0 missorting and aggregation of GPI-anchored GFP-CD59 in the cytoplasm of HeLa cells upon CTD treatment, which was very similar to that of Gas1-GFP in yeast. Similarly, CTD also induced phosphorylation of p44/42 (yeast Slt2), supporting the previous observations of CTD-mediated activation of different MAPKs (18,21). We also found decreased expression of XBP1 (yeast HAC1) upon CTD treatment which might be via ATF6 signaling that regulates the target gene XBP1 (65).…”

“…The inhibition of PP2A causes cell cycle arrest (25,26) and apoptosis (27,28). CTD also impairs different cellular processes such as heat shock response (29), autophagy (22), DNA damage response, and mitogen-activated protein kinase (MAPK) signaling (18,21). One of these studies also demonstrated a PP2A or PP1 independent alteration in heat shock response (29), suggesting the existence of additional molecular targets of CTD (29,30).…”

“…In the last few decades, many studies have demonstrated the anticancer property of CTD. It has been shown to inhibit the growth of hepatocellular carcinoma (16), leukemia (17), pancreatic (18), colorectal (19), gallbladder (20), oral (21), and breast cancer (22). The serine-threonine protein phosphatases, PP1 and PP2A, are the only reported molecular targets of CTD (23,24).…”