Honokiol induces paraptosis-like cell death of acute promyelocytic leukemia via mTOR & MAPK signaling pathways activation

Abstract

Acute promyelocytic leukemia (APL) is a blood system disease caused by the accumulation of a large number of immature blood cells in bone marrow. Although the introduction of all-trans retinoic acid (ATRA) and arsenic has reached a high level of complete remission rate and 5-year disease-free survival rate, the occurrence of various adverse reactions still severely affects the quality of life of patients. As a natural product, honokiol (HNK) has the advantages of low toxicity and high efficiency, and it is a potential drug for the treatment of cancer. Since cancer cells can escape apoptotic cell death through multiple adaptive mechanisms, HNK, a drug that induces cancer cell death in a nonapoptotic way, has attracted much interest. We found that HNK reduced the viability of human APL cell line (NB4 cells) by inducing paraptosis-like cell death. The process was accompanied by excessive reactive oxygen species (ROS), mitochondrial damage, endoplasmic reticulum stress, and increased microtubule-associated protein 1 light chain 3 (LC3) processing. The inactivation of proteasome activity was the main cause of misfolded and unfolded protein accumulation in endoplasmic reticulum, such as LC3II/I and p62. This phenomenon could be alleviated by adding cycloheximide (CHX), a protein synthesis inhibitor. We found that mTOR signaling pathway participated in paraptosis-like cell death induced by HNK in an autophagy-independent process. Moreover, the mitogen-activated protein kinase (MAPK) signaling pathway induced paraptosis of NB4 cells by promoting endoplasmic reticulum stress. In summary, these findings indicate that paraptosis may be a new way to treat APL, and provide novel insights into the potential mechanism of paraptosis-like cell death.

Glabridin induces paraptosis-like cell death via ER stress in breast cancer cells

“…We observed that the vacuoles induced by glabridin grow progressively in size with increasing concentration and duration, eventually fusing into giant vacuoles. Moreover, in line with previous studies [ 11 , 12 ], vacuole formation could be effectively prevented by pretreatment with the protein synthesis inhibitor cycloheximide. Simultaneously, we found that glabridin treatment elevated the expression levels of ER stress markers such as BiP, XBP1s, and CHOP in a time- and concentration-dependent manner, and that this increase happened at the same time as the appearance of cytoplasmic vacuolation.…”

“…Interestingly, extensive cytoplasmic vacuolation was observed in all four breast cancer cell lines (Figure 2A and Figure S2). These vacuoles resemble those produced by honokiol [11] or curcumin [12], both of which have been shown to induce paraptosis (Figures S3 and S4). Moreover, the number of vacuoles grows and fuses together as the concentration of Glabridin increases (Figure 2A).…”

“…Multifarious natural and synthetic compounds have been found to induce paraptosis in cancer cells [ 11 , 12 , 13 , 14 , 15 ]. Glabridin (GLA) is a polyphenolic flavonoid originally isolated from the root of glycyrrhiza glabra (licorice) [ 16 ].…”

Glabridin induces paraptosis-like cell death via ER stress in breast cancer cells

“…Multifarious natural and synthetic compounds have been found to induce paraptosis in cancer cells [11][12][13][14][15]. Glabridin (GLA) is a polyphenolic flavonoid originally isolated from the root of glycyrrhiza glabra (licorice) [16].…”

Programmed cell death lives

“…However, over the years, it has become increasingly clear that additional forms of programmed cell deaths are involved in the anti-tumor activity of different synthetic and natural compounds [ 7 , 8 ]. Specifically, paraptosis is a type of non-canonical programmed cell death characterized by a peculiar cytoplasmic vacuolation, associated with endoplasmic reticulum (ER) dilatation and mitochondrial swelling [ 9 ]. It was previously demonstrated that the vitamin E derivative δ-tocotrienol (δ-TT) triggers ER stress-mediated apoptosis in human melanoma cells [ 10 ].…”