Curcumin Induces Apoptosis of Chemoresistant Lung Cancer Cells via ROS-Regulated p38 MAPK Phosphorylation

Abstract

This study aimed to challenge chemoresistance by curcumin (CUR) with drug-selected human lung cancer A549 sublines that continuously proliferate in the present of docetaxel (DOC) and vincristine (VCR). Their sensitivities to CUR were measured by MTT assay and the particular intracellular reactive oxygen species (ROS) was detected by fluorescence activated cell sorting (FACS) analysis. Apoptosis was analyzed by Annexin V assay of the flow cytometry. Inhibitors and RNA interference were used to examine the signaling pathway regulated by the kinases. The obtained data demonstrated that CUR induces chemoresistant cell apoptosis by generating ROS and application of N-acetylcysteine (NAC) blocks ROS production, resulting in apoptosis suppression. Phosphorylation of extracellular regulated kinase (ERK), p38 MAPK, and eIF-2α were increased but c-Jun N-terminal kinase (JNK) did not increase when chemoresistant cells were treated with CUR. Downregulation of ERK and p38 MAPK phosphorylation by their inhibitors had no effect on CUR-induced apoptosis. Interestingly, the knockdown of p38 MAPK with shRNA significantly reduced CUR-induced apoptosis on the chemoresistant sublines. Phosphorylation of the eIF-2α protein was inhibited when p38 MAPK was knocked down in DOC-resistant A549 cells, but a high level of phosphorylated eIF-2α protein remained on the VCR-resistant A549 cells when p38 MAPK was knocked down. These data confirmed that CUR-augmented ROS potently induced apoptosis via upregulated p38 MAPK phosphorylation. Therefore, activated p38 MAPK is considered a pro-apoptotic signal for CUR-induced apoptosis of chemoresistant human lung cancer cells.

PD-1/LAG-3 Dysfunctionality Signatures in Human Cancers

“…For example, downmodulation of the MAPK and EIF2 signalling pathways, supported by previous studies that proposed CBL-B and C-CBL as negative regulators of MAPKs (Kales et al, 2014; Qu et al, 2011; Zhang et al, 2004; Zhao et al, 2013). Negative regulation of the MAPK pathway would disrupt phosphorylation of eukaryotic translation initiation factor, resulting in inhibition of EIF2 signalling (Siraj et al, 2022; Tian et al, 2011; Wu et al, 2022). Notably, although PD-1 has been broadly linked to CBL expression in T-cells (Babu et al, 2006; Karwacz et al, 2011; Kumar et al, 2021; Nguyen et al, 2021; Peer et al, 2017), LAG-3 expression has never been associated to CBL ubiquitin ligases before.…”

Realgar‑induced KRAS mutation lung cancer cell death via KRAS/Raf/MAPK mediates ferroptosis

“…According to Huang et al ( 52 ), arsenic trioxide (ATO)-induced p38 MAPK overexpression promotes apoptosis in K562 and MEG-01 cells. According to Wu et al ( 53 ), activated p38 MAPK is a pro-apoptotic signal for curcumin-induced mortality of chemoresistant human lung cancer cells A549. Theabrownin, a component of green tea, suppresses human NSCLC in a xenograft model via activating the MAPK/JNK signaling pathway, according to Xiao et al ( 54 ).…”

The Involvement of Natural Polyphenols in Molecular Mechanisms Inducing Apoptosis in Tumor Cells: A Promising Adjuvant in Cancer Therapy

“…However, human epidemiological studies are not having much success in evaluating polyphenols’ effects due to their poor bioavailability and high metabolism rate [ 32 ]. Accumulating data showed in vitro polyphenols anti-proliferative effects on several cancer types, such as prostate [ 33 , 34 ], colon [ 35 , 36 ], breast [ 37 , 38 , 39 ], lung [ 40 , 41 ], bladder [ 42 , 43 ], pancreatic [ 44 , 45 ], leukemia [ 46 , 47 ], osteosarcoma [ 48 , 49 ] and ovarian [ 50 , 51 ], through different mechanisms of action. They can influence important molecular events related to carcinogenesis; these include the modulation of cell cycle signaling, induction of detoxifying and antioxidant enzyme systems, alteration of the epigenome and metabolism, and changes in the expression of key proteins involved in signal transduction pathways (e.g., MAPK and PI3K) or in the activity of transcription factors (e.g., NFkB) [ 52 , 53 , 54 ].…”