TIGAR knockdown enhanced the anticancer effect of aescin via regulating autophagy and apoptosis in colorectal cancer cells

Abstract

Our previous study showed that TP53-induced glycolysis and apoptosis regulator (TIGAR) regulated ROS, autophagy, and apoptosis in response to hypoxia and chemotherapeutic drugs. Aescin, a triterpene saponin, exerts anticancer effects and increases ROS levels. The ROS is a key upstream signaling to activate autophagy. Whether there is a crosstalk between TIGAR and aescin in regulating ROS, autophagy, and apoptosis is unknown. In this study, we found that aescin inhibited cell viability and colony formation, and induced DNA damage, cell cycle arrest, and apoptosis in cancer cell lines HCT-116 and HCT-8 cells. Concurrently, aescin increased the expression of TIGAR, ROS levels, and autophagy activation. Knockdown of TIGAR enhanced the anticancer effects of aescin in vitro and in vivo, whereas overexpression of TIGAR or replenishing TIGAR downstream products, NADPH and ribose, attenuated aescin-induced apoptosis. Furthermore, aescin-induced ROS elevation and autophagy activation were further strengthened by TIGAR knockdown in HCT-116 cells. However, autophagy inhibition by knockdown of autophagy-related gene ATG5 or 3-methyladenine (3-MA) exaggerated aescin-induced apoptosis when TIGAR was knocked down. In conclusion, TIGAR plays a dual role in determining cancer cell fate via inhibiting both apoptosis and autophagy in response to aescin, which indicated that inhibition of TIGAR and/or autophagy may be a junctional therapeutic target in treatment of cancers with aescin.

Targeted p53 on Small-Molecules-Induced Ferroptosis in Cancers

“…Nevertheless, in mouse models, the absence of TIGAR reduces capabilities to regenerate injured intestinal epithelium and represses tumor development with ROS restriction ( 50 ). TIGAR is upregulated in some cancer models and tumor types via a pattern that may be independent on the maintenance of p53 ( 51 , 52 ). Furthermore, TIGAR expression negatively correlates with p53 expression in human breast cancer ( 53 ).…”

Higher plasma concentration of TP53-induced glycolysis and apoptosis regulator is associated with a lower risk of colorectal cancer metastasis

“…TIGAR acted as an oncogene in nasopharyngeal carcinoma (NPC) tumorigenesis, and knockdown of TIGAR inhibited tumor growth via activation of NF-κB pathway 20. Deletion of TIGAR sensitizes cancer cells to radiotherapy and chemotherapy in glioma and CRC cells 9,21. When over-expressed, TIGAR protects chronic lymphocytic leukemia (CLL) cells from spontaneous apoptosis and is closely correlated with worse clinical outcome in CLL patients 13.…”

“…Functioning like FBPase-2, TIGAR lowers intracellular fructose 2,6-biphosphate (FBP) levels, thus decreases the glycolytic rate and diverts the glucose metabolism to the pentose phosphate pathway (PPP) 8. Increased expression of TIGAR mRNA and protein was associated with cancer cell survival and metastasis in many cancers,9–13 while the association between plasma TIGAR concentration and CRC metastasis remains unclear. In the present study, we aimed to explore the association of plasma TIGAR concentration with CRC metastasis and the prognostic value of TIGAR as a potential marker for CRC metastasis.…”

The Role of TIGAR-mediated Metabolic Processes in Autophagy and Cell Survival

“…TIGAR is a multifunctional protein that is not only involved in the regulation of glucose metabolism, cell cycle progression and radiation response, but also in autophagy [17]. A number of studies have shown that autophagy is inhibited by overexpression of TIGAR and induced by knockdown of TIGAR [8,[29][30][31] and TIGAR-regulated autophagy is closely related to clinical disease. For example, TIGAR inhibits proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) by inhibiting autophagy and ROS, thereby improving hypoxia-induced pulmonary arterial hypertension (PAH) [32].…”