SIRT3, PP2A and TTP protein stability in the presence of TNF‐α on vincristine‐induced apoptosis of leukaemia cells

Abstract

The contribution of vincristine (VCR)‐induced microtubule destabilization to evoke apoptosis in cancer cells remains to be resolved. Thus, we investigated the cytotoxic mechanism of VCR on U937 and HL‐60 human leukaemia cell lines. We discovered that VCR treatment resulted in the up‐regulation of TNF‐α expression and activation of the death receptor pathway, which evoked apoptosis of U937 cells. Moreover, VCR induced microtubule destabilization and mitotic arrest. VCR treatment down‐regulated SIRT3, and such down‐regulation caused mitochondrial ROS to initiate phosphorylation of p38 MAPK. p38 MAPK suppressed MID1‐modulated degradation of the protein phosphatase 2A (PP2A) catalytic subunit. The SIRT3‐ROS‐p38 MAPK‐PP2A axis inhibited tristetraprolin (TTP)‐controlled TNF‐α mRNA degradation, consequently, up‐regulating TNF‐α expression. Restoration of SIRT3 and TTP expression, or inhibition of the ROS‐p38 MAPK axis increased the survival of VCR‐treated cells and repressed TNF‐α up‐regulation. In contrast to suppression of the ROS‐p38 MAPK axis, overexpression of SIRT3 modestly inhibited the effect of VCR on microtubule destabilization and mitotic arrest in U937 cells. Apoptosis of HL‐60 cells, similarly, went through the same pathway. Collectively, our data indicate that the SIRT3‐ROS‐p38 MAPK‐PP2A‐TTP axis modulates TNF‐α expression, which triggers apoptosis of VCR‐treated U937 and HL‐60 cells. We also demonstrate that the apoptotic signalling is not affected by VCR‐elicited microtubule destabilization.

Phytoestrogen arctigenin preserves the mucus barrier in inflammatory bowel diseases by inhibiting goblet cell apoptosis via the ERβ/TRIM21/PHB1 pathway

“…Prohibitin (PHB) 1 is a mitochondrial inner‐membrane protein which involved in mitochondrial homeostasis and related to the cell apoptosis mediated by the mitochondrial pathway (Wang, Chiou, et al, 2020, Wang, Zhu, et al, 2020; Tao et al, 2021, Zhang et al, 2020). Herein, we investigated the effect of actigenin and DPN on the expression of PHB1 in LS174T cells.…”

Sirt3 Protects Against Thoracic Aortic Dissection Formation by Reducing Reactive Oxygen Species, Vascular Inflammation, and Apoptosis of Smooth Muscle Cells

“…In addition, the literature also shows that the lack of Sirt3 can enhance the P38 MAPK pathway. For example, in the experiment of vincristine (VCR) inducing tumor cell apoptosis, one of the mechanisms may be that VCR downregulates the expression of Sirt3, which in turn leads to the accumulation of mitochondrial ROS and initiates the phosphorylation of p38 MAPK and upregulates the expression of TNF-α, which ultimately leads to the apoptosis of U937 and HL-60 cells (36). Moreover, the activation of P38 MAPK also plays an important role in the process of aortic remodeling.…”

Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies

“…As mentioned in Section 5 above, vincristine destabilizes microtubules through suppression of tubulin polymerization [180]. As a result, cells undergo arrest in the G2/M phase.…”