Down-Regulation of Tumor-Associated NADH Oxidase, tNOX (ENOX2), Enhances Capsaicin-Induced Inhibition of Gastric Cancer Cell Growth

Abstract

Gastric cancer is a common human malignancy and a major contributor to cancer-related deaths worldwide. Unfortunately, the prognosis of most gastric cancer patients is poor because they are generally diagnosed at a late stage after the cancer has already metastasized. Most current research, therefore, emphasizes selective targeting of cancer cells by apoptosis-inducing agents. One such therapeutic agent is capsaicin, a component of chili peppers that has been shown to possess anti-growth activity against various cancer cell lines. Here, we examined the effect of capsaicin on SNU-1 and TMC-1 gastric cancer cells and found differing outcomes between the two cell lines. Our results show that capsaicin induced significant cytotoxicity with increases in oxidative stress, PARP cleavage, and apoptosis in sensitive SNU-1 cells. In contrast, TMC-1 cells were much less sensitive to capsaicin, exhibiting low cytotoxicity and very little apoptosis in response to capsaicin treatment. Capsaicin-induced apoptosis in SNU-1 cells was associated with down-regulation of tumor-associated NADH oxidase (tNOX) mRNA and protein. On the contrary, tNOX expression was scarcely affected by capsaicin in TMC-1 cells. We further showed that tNOX-knockdown sensitized TMC-1 cells to capsaicin-induced apoptosis and G1 phase accumulation, and led to decreased cell growth, demonstrating that tNOX is essential for cancer cell growth. Collectively, these results indicate that capsaicin induces divergent effects of the growth of gastric cancer cells that parallel its effects on tNOX expression, and demonstrate that forced tNOX down-regulation restored capsaicin-induced growth inhibition in TMC-1 cells.

A Comprehensive Review of the Carcinogenic and Anticarcinogenic Potential of Capsaicin

“…In pure mitochondria, inhibited mitochondrial complex-I and complex-III, but not in normal cells Tumors from mice fed orally 2.5 mg/kg capsaicin showed decreased SOD activity and increased ratio of oxidized glutathione to glutathione Wang et al 2011 Human SNU-1 and TMC-1 gastric normal cells. For instance, Richeux et al (1999) reported that cytotoxicty and DNA fragmentation was induced in human neuroblastoma SHSY-5Y cells by 25-100 mM capsaicin, with an IC 50 of 60 mM for the inhibition of protein synthesis.…”

Sirtuin 1 (SIRT1) Deacetylase Activity and NAD+/NADH Ratio Are Imperative for Capsaicin-Mediated Programmed Cell Death

“…In fact, we previously discovered that capsaicin has divergent effects on the growth of gastric cancer cells that parallel its effects on tNOX expression, apoptosis in association with reduced tNOX expression in SNU-1 gastric cancer cells, and little apoptosis accompanied by insignificant changes in tNOX in the TMC-1 metastatic gastric carcinoma line. 4 However, whether the intracellular NAD + /NADH ratio also contributed to the different cellular responses between these two gastric cancer lines was not examined. Experiments utilizing tNOX-knockdown cells showed that tNOX-depletion decreased the intracellular NAD + /NADH ratio compared to that in control cells ( Figure 5), further confirming a regulatory role of tNOX in maintaining the NAD + /NADH redox status.…”

Capsaicin induces apoptosis and modulates MAPK signaling in human gastric cancer cells

“…The molecular mechanisms underlying capsaicin-induced apoptosis are cell-type dependent. Despite the cumulative evidence for the tumor suppressive effects of capsaicin, few studies have been undertaken concerning the effects of capsaicin on cell signaling and molecular pathways leading to apoptosis in gastric cancer (10)(11)(12).…”