Molecular mechanism underlying the apoptotic modulation by ethanol extract of Pseudolarix kaempferi in mucoepidermoid carcinoma of the salivary glands

Abstract

Background Pseudolarix kaempferi is a traditional Chinese natural product that possesses the potential cytotoxic effects against cancer. However, the precise molecular mechanism underlying its cytotoxic effects has not yet been completely elucidated. Here, we clarify the mechanism via which the ethanol extract of P. kaempferi (EEPK) leads to cytotoxicity mediated by apoptosis in mucoepidermoid carcinoma (MEC) originating from the salivary glands. Methods We investigated the mechanism underlying the anticancer efficacy of EEPK in human MEC in vitro by assessing mitochondrial dysfunction, mRNA levels, and morphological changes in apoptotic cell nuclei as well as by using a cytotoxicity assay, flow cytometric analysis, and western blotting. Results EEPK inhibited the growth of two human MEC cells and stimulated the induction of caspase-mediated apoptosis that was accompanied by mitochondrial membrane depolarization. Compared with the vehicle control groups, EEPK decreased myeloid cell leukemia-1 (Mcl-1) expression in both cells whereas it significantly decreased B cell lymphoma-2 (Bcl-2) expression in MC3 cells only. The EEPK-induced altered Mcl-1 expression was caused by translational inhibition and proteasomal degradation. Additionally, EEPK significantly increased p-Bcl-2 (Ser70) expression regardless of its total forms by facilitating the activation of the c-Jun N-terminal kinase (JNK) signaling pathway, which exhibited cell context dependency. Nevertheless, JNK activation following EEPK treatment was, at least in part, required for the proapoptotic efficacy of EEPK in both cells. Conclusions This study revealed that EEPK-induced alterations of Mcl-1 inhibition and JNK/Bcl-2 phosphorylation cause apoptosis and provided basic preclinical data for future clinical trials regarding therapy for patients with MEC. Graphic abstract

Podophyllotoxin reduces the aggressiveness of human oral squamous cell carcinoma through myeloid cell leukemia‑1

“…Mcl-1 mRNA levels were unchanged following PPT treatment, which ruled out the possibility that PPT affected the transcriptional regulation of Mcl-1. Numerous studies have demonstrated that decreased Mcl-1 expression, which may be caused by various compounds in cancer cells, is dependent on proteasomal processes ( 23 , 51 ). Thus, it is hypothesized that PPT induces a rapid turnover of Mcl-1 protein in OSCC cell lines.…”

Caffeic acid phenethyl ester: Unveiling its potential as a potent apoptosis inducer for combating hypopharyngeal squamous cell carcinoma

“…These two apoptotic pathways eventually converge toward the formation of cleaved caspase-3 and, finally, cleaved PARP, followed by cell demise (20). Several natural products exert tumor-inhibitory activities by stimulating the intrinsic and extrinsic apoptotic signaling pathways exclusively, respectively, or by triggering the two pathways simultaneously (36)(37)(38). In the latter cellular context, the intrinsic and extrinsic apoptotic pathways can be integrated through the truncation of the BH3 interacting domain death agonist (Bid) protein, which is a process that is facilitated by c-caspase-8 (39).…”