Paclitaxel induces apoptosis through the TAK1–JNK activation pathway

Di, Yuwei; Li, Zhuo-Sheng; Xiong, Shangwu; Huang, Ge; Luo, Yan; Huo, Tie-Ying; Zhou, Mi; Zheng, Yi

doi:10.1002/2211-5463.12917

Cited by 18 publications

(11 citation statements)

References 33 publications

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“…Interestingly, under Pac stimulatory conditions in HEK293 cells, Bcl-xl protein levels (in relation to p21 BAX protein levels) were observed to diminish ( Supplementary Figure S3B ). As reported in previous studies, this may be due to dose- and time-dependent responsiveness of cells to Pac, as seen with 8305C cells [ 39 ]. Moreover, down-regulation of Bcl-xl, has been reported upon the treatment of prostate cells with Docetaxel [ 40 , 41 ] or under oxidative stress conditions, in a Keap1 adaptor protein-dependent manner [ 42 ], and cannot be excluded as contributory factors.…”

Section: Resultssupporting

confidence: 51%

Cathepsin S Cleaves BAX as a Novel and Therapeutically Important Regulatory Mechanism for Apoptosis

et al. 2021

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Certain lysosomal cathepsin proteins have come into focus as being good candidates for therapeutic targeting, based on them being over-expressed in a variety of cancers and based on their regulation of the apoptotic pathway. Here, we report novel findings that highlight the ability of cathepsin S expression to be up-regulated under Paclitaxel-stimulatory conditions in kidney cell lines and it being able to cleave the apoptotic p21 BAX protein in intact cells and in vitro. Consistent with this, we demonstrate that this effect can be abrogated in vitro and in mammalian cells under conditions that utilize dominant-inhibitory cathepsin S expression, cathepsin S expression-knockdown and through the activity of a novel peptide inhibitor, CS-PEP1. Moreover, we report a unique role for cathepsin S in that it can cleave a polyubiquitinated-BAX protein intermediate and is a step that may contribute to down-regulating post-translationally-modified levels of BAX protein. Finally, CS-PEP1 may possess promising activity as a potential anti-cancer therapeutic against chemotherapeutic-resistant Renal Clear Cell Carcinoma kidney cancer cells and for combined uses with therapeutics such as Paclitaxel.

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Section: Resultssupporting

confidence: 51%

Cathepsin S Cleaves BAX as a Novel and Therapeutically Important Regulatory Mechanism for Apoptosis

et al. 2021

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“…JNK is a common target and is phosphorylated and activated by the four drugs (illustrated in Figure 6E and 49 , 50 , 51 , 52 ). We thus examined whether JNK is involved in the nuclear translocation of RB1CC1.…”

Section: Resultsmentioning

confidence: 99%

Tumour cells are sensitised to ferroptosis via RB1CC1‐mediated transcriptional reprogramming

Xue

Zhang

et al. 2022

Clinical & Translational Med

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Background Ferroptosis, a form of regulated cell death, is an important topic in the field of cancer research. However, the signalling pathways and factors that sensitise tumour cells to ferroptosis remain elusive. Methods We determined the level of ferroptosis in cells by measuring cell death and lipid reactive oxygen species (ROS) production. The expression of RB1‐inducible coiled‐coil 1 (RB1CC1) and related proteins was analyzed by immunoblotting and immunohistochemistry. Immunofluorescence was used to determine the subcellular localization of RB1CC1. We investigated the mechanism of RB1CC1 nuclear translocation by constructing a series of RB1CC1 variants. To examine the ferroptosis‐ and RB1CC1‐dependent transcriptional program in tumour cells, chromatin immunoprecipitation sequencing was performed. To assess the effect of c‐Jun N‐terminal kinase (JNK) agonists on strenthening imidazole ketone erastin (IKE) therapy, we constructed cell‐derived xenograft mouse models. Mouse models of hepatocellular carcinoma to elucidate the importance of Rb1cc1 in IKE‐based therapy of liver tumourigenesis. Results RB1CC1 is upregulated by lipid ROS and that nuclear translocation of phosphorylation of RB1CC1 at Ser537 was essential for sensitising ferroptosis in tumour cells. Upon ferroptosis induction, nuclear RB1CC1 sharing forkhead box (FOX)‐binding motifs recruits elongator acetyltransferase complex subunit 3 (ELP3) to strengthen H4K12Ac histone modifications within enhancers linked to ferroptosis. This also stimulated transcription of ferroptosis‐associated genes, such as coiled‐coil–helix–coiled‐coil–helix domain containing 3 (CHCHD3), which enhanced mitochondrial function to elevate mitochondrial ROS early following induction of ferroptosis. FDA‐approved JNK activators reinforced RB1CC1 nuclear translocation and sensitised cells to ferroptosis, which strongly suggested that JNK is upstream of RB1CC1. Nuclear localisation of RB1CC1 correlated with lipid peroxidation in clinical lung cancer specimens. Rb1cc1 was essential for ferroptosis agonists to suppress liver tumourigenesis in mice. Conclusions Our findings indicate that RB1CC1‐associated signalling sensitises tumour cells to ferroptosis and that targeting RB1CC1 may be beneficial for tumour treatment.

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“…The caspase activation is a major leading cause to apoptosis (38), including effector (caspase-3) and initiator (caspase-8) (39,40). poly ADP-ribose polymerase (PARP) is a DNA-binding enzyme involved in apoptosis (41,42). Bax is a direct target in p53-mediated apoptosis (43).…”

Section: Discussionmentioning

confidence: 99%

lncRNA EGFEM1P promotes thyroid cancer progression by acting as an miR‑369‑3p sponge and upregulating TCF4

Liu

Chen

2022

Oncol Lett

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Thyroid cancer is the most commonly diagnosed endocrine cancer, with the incidence of 14.42 per 100,000 person-years in 2010-2013. It is important to conduct an in-depth exploration into the molecular mechanisms of thyroid cancer, providing insights into the improvements of therapy. Long non-coding RNAs (lncRNAs) act as oncogenes or tumor suppressors in thyroid cancer by sponging microRNAs (miRNAs), however, the functions of numerous lncRNAs are still unknown. In the present study, via the comprehensive analysis of microarray data derived from papillary thyroid tumors and the RNA sequencing of thyroid tumors from The Cancer Genome Atlas database, EGF like and EMI domain containing 1 (EGFEM1P) expression levels in papillary thyroid tumors and normal adjacent tissues were explored. Reverse transcription-quantitative PCR was used to detect EGFEM1P, microRNA (miR)-369-3p and T cell factor 4 (TCF4) expression levels. Western blotting was used to detect TCF4 protein and cleaved caspase-3/8 expression levels. Cell proliferative ability and apoptosis were assessed using the Cell Counting Kit-8 assay and flow cytometry, respectively. The interactions between EGFEM1P and miR-369-3p, and miR-369-3p and TCF4, were determined using the dual-luciferase reporter assay. The results demonstrated that EGFEM1P was upregulated in papillary thyroid tumors and thyroid cancer cells compared with normal adjacent tissues and human normal thyroid epithelial Nthy-ori 3-1 cell line. In the examined thyroid cancer cells, EGFEM1P was demonstrated to interact with miR-369-3p and decreased miR-369-3p expression levels. Thereafter, TCF4 was determined to be a target gene of miR-369-3p and EGFEM1P promoted TCF4 expression via regulating miR-369-3p expression levels. At last, it was found that EGFEM1P expression promoted rapid cell proliferation and inhibited cell apoptosis in thyroid cancer cells via acting as a miR-369-3p sponge. In conclusion EGFEM1P promoted thyroid cancer progression via acting as a sponge of the miR-369-3p/TCF4 axis.

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Paclitaxel induces apoptosis through the TAK1–JNK activation pathway

Cited by 18 publications

References 33 publications

Cathepsin S Cleaves BAX as a Novel and Therapeutically Important Regulatory Mechanism for Apoptosis

Cathepsin S Cleaves BAX as a Novel and Therapeutically Important Regulatory Mechanism for Apoptosis

Tumour cells are sensitised to ferroptosis via RB1CC1‐mediated transcriptional reprogramming

lncRNA EGFEM1P promotes thyroid cancer progression by acting as an miR‑369‑3p sponge and upregulating TCF4

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