Betulinic Acid Inhibits Cell Proliferation in Human Oral Squamous Cell Carcinoma via Modulating ROS-Regulated p53 Signaling

Abstract

Oral squamous cell carcinoma (OSCC) is a common cancer of the head and neck. Betulinic acid (BA) is a naturally occurring pentacyclic triterpenoid. The present study was designed to explore the effects of BA on OSCC KB cell proliferation in vitro and on implanted tumor growth in vivo and to examine the possible molecular mechanisms. The results showed that BA dose-dependently inhibited KB cell proliferation and decreased implanted tumor volume. In addition, BA significantly promoted mitochondrial apoptosis, as reflected by an increase in TUNEL+ cells and the activities of caspases 3 and 9, an increase in Bax expression, and a decrease in Bcl-2 expression and the mitochondrial oxygen consumption rate. BA significantly increased cell population in the G0/G1 phase and decreases the S phase cell number, indicating the occurrence of G0/G1 cell cycle arrest. ROS generation was significantly increased by BA, and antioxidant NAC treatment markedly inhibited the effect of BA on apoptosis, cell cycle arrest, and proliferation. BA dose-dependently increased p53 expression in KB cells and implanted tumors. p53 reporter gene activity and p53 binding in the promoters of Bax were significantly increased by BA. Knockdown of p53 blocked BA-induced increase in apoptosis, cell cycle arrest, and inhibition of cell proliferation. NAC treatment suppressed BA-induced increase in p53 expression. Furthermore, phosphorylation of signal transducer and activator of transcription 3 (STAT3) was increased by BA. Taken together, the data demonstrated that ROS-p53 signaling was crucial for BA-exhibited antitumor effect in OSCC. BA may serve as a potential drug for the treatment of oral cancer.

Role and regulation of proapoptotic Bax in oral squamous cell carcinoma and drug resistance

“…P53, a well‐known tumor suppressor protein is involved in the induction of Bax‐mediated apoptosis, whereas mutant p53 is associated with cisplatin resistance in oral cancer . P53 regulates the transcription of Bax gene and the loss of p53 function causes diminished expression of Bax .…”

Autophagy inhibitor facilitates gefitinib sensitivity in vitro and in vivo by activating mitochondrial apoptosis in triple negative breast cancer

“…DNA damage signal was transmitted by ATM to downstream targets including p-Chk1 and p-Chk2 which played an important role in cell cycle regulation [48–51]. When autophagy was blocked, damaged mitochondria would release ROS and induce of G0/G1 cell cycle arrest [26, 52], causing oxidation of DNA and resulting in DNA damage. In this study, we found that as the measure molecular of DNA damage, the expression of γ-H2AX, ATM, p-Chk1 and p-Chk2 were increased when Ge and autophagy inhibitor combined.…”

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

“…Besides, some reports revealed that betulinic acid could regulate STAT3 in many cancer types [51,52]. In central nervous system cancer cell lines, compounds nakiterpiosin and cucurbitacin I had a positive correlation coefficient greater than 0.3 (higher expression of STAT3 related to resistance).…”