Pristimerin Induces Autophagy‐Mediated Cell Death in K562 Cells through the ROS/JNK Signaling Pathway

Abstract

Chronic myeloid leukemia (CML) is a lethal malignancy, and the progress toward long‐term survival has stagnated in recent decades. Pristimerin, a quinone methide triterpenoid isolated from the Celastraceae and Hippocrateaceae families, is well‐known to exert potential anticancer activities. In this study, we investigated the effects and the mechanisms of action on CML. We found that pristimerin inhibited cell proliferation of K562 CML cells by causing G1 phase arrest. Furthermore, we demonstrated that pristimerin triggered autophagy and apoptosis. Intriguingly, pristimerin‐induced cell death was restored by an autophagy inhibitor, suggesting that autophagy is cross‐linked with pristimerin‐induced apoptosis. Further studies revealed that pristimerin could produce excessive reactive oxygen species (ROS), which then induce JNK activation. These findings provide clear evidence that pristimerin might be clinical benefit to patients with CML.

Curcumin induces G2/M arrest and triggers autophagy, ROS generation and cell senescence in cervical cancer cells

“…It is regulated and induced by multiple factors, among which the ROS-JNK pathway is one of the most important 25 . Once activated by ROS, JNK1 can directly phosphorylate Bcl-2 protein and dissociate it from Beclin 1, thereby initiating autophagy 26 , 27 . In addition, the ROS-JNK signaling pathway can induce autophagy by directly upregulating the key autophagy genes autophagy gene 7 (ATG7) and ATG5 through a Beclin1-independent mechanism 28 .…”

“…Siha cells were plated at a density of 1.0×10 6 cells/well into 6-well flat-bottom tissure culture plates and treated with different concentrations of curcumin (30 and 50 µM) or vehicle control DMSO for 24 h, or with Cur 50 µM + NAC. After the treatment, the cells were harvested, washed twice with ice cold PBS (pH 7.4) and fixed in 70% ethanol for overnight at 4 °C.…”

“…In the past, ROS were generally thought to be merely toxic by-products of aerobic metabolism. However, recent studies have indicated that ROS can act as signaling molecules and play crucial roles in diverse signal transduction pathways [5,6]. Autophagy is a recycling system whereby cells degrade cytoplasmic proteins and organelles through the lysosomal pathway [7].…”

“…ROS and autophagy-related proteins, which regulate the autophagic response to cellular stress, counterbalance each other via multiple complex signaling pathways [9]. Under certain circumstances, ROS can also induce cellular damage and perturb specific signal transduction pathways, thereby leading to autophagic cell death, also termed Type II cell death [10]. In addition, ROS are important components of the c-Jun N-trminal kinase (JNK) signaling pathway and thus play vital roles in the inflammatory response and apoptosis.…”

Cellular and Molecular Mechanisms of Pristimerin in Cancer Therapy: Recent Advances

“…Emerging evidence has shown that pristimerin treatment gives rise to cell accumulation in G0/G1 phases and cell reduction in S and G2/M phases, indicating the induction of G0/G1 phase arrest to exhibit anti-proliferative effects on various cancers including CRC (22,38), breast cancer (9,21), uveal melanoma (UM) (18,23,30), chronic myelogenous leukemia (CML) (39), oral squamous cell carcinoma (OSCC) (27), esophageal cancer (40), pancreatic cancer (26,41), prostate cancer (24,25) and cholangiocarcinoma (42). However, a study related to the imatinib-resistant CML has found that pristimerin does not significantly affect the cell cycle other than the emergence of cells in the sub-G1 apoptotic phase (43).…”