BIOMAT Database Logo BIOMAT Database Logo

Oxidative Stress-Induced Unscheduled CDK1-Cyclin B1 Activity Impairs ER-Mitochondria-Mediated Bioenergetic Metabolism. 2021

Jan-Gowth Chang, and Ni Tien, and Yi-Chih Chang, and Meng-Liang Lin, and Shih-Shun Chen
Department of Laboratory Medicine, China Medical University Hospital, Taichung 404394, Taiwan.

Targeting the activities of endoplasmic reticulum (ER)-mitochondrial-dependent metabolic reprogramming is considered one of the most promising strategies for cancer treatment. Here, we present biochemical subcellular fractionation, coimmunoprecipitation, gene manipulation, and pharmacologic evidence that induction of mitochondria-localized phospho (p)-cyclin dependent kinase 1 (CDK1) (Thr 161)-cyclin B1 complexes by apigenin in nasopharyngeal carcinoma (NPC) cells impairs the ER-mitochondrial bioenergetics and redox regulation of calcium (Ca++) homeostasis through suppressing the B cell lymphoma 2 (BCL-2)/BCL-2/B-cell lymphoma-extra large (BCL-xL)-modulated anti-apoptotic and metabolic functions. Using a specific inducer, inhibitor, or short hairpin RNA for acid sphingomyelinase (ASM) demonstrated that enhanced lipid raft-associated ASM activity confers alteration of the lipid composition of lipid raft membranes, which leads to perturbation of protein trafficking, and induces formation of p110α free p85α-unphosphorylated phosphatase and tensin homolog deleted from chromosome 10 complexes in the lipid raft membranes, causing disruption of phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-GTP-ras-related C3 botulinum toxin substrate 1 (Rac1)-mediated signaling, thus triggering the p-CDK1 (Thr 161))-cyclin B1-mediated BCL-2 (Thr 69/Ser 87)/BCL-xL (Ser 62) phosphorylation and accompanying impairment of ER-mitochondria-regulated bioenergetic, redox, and Ca++ homeostasis. Inhibition of apigenin-induced reactive oxygen species (ROS) generation by a ROS scavenger N-acetyl-L-cysteine blocked the lipid raft membrane localization and activation of ASM and formation of ceramide-enriched lipid raft membranes, returned PI3K-Akt-GTP-Rac1-modulated CDK1-cyclin B1 activity, and subsequently restored the BCL-2/BCL-xL-regulated ER-mitochondrial bioenergetic activity. Thus, this study reveals a novel molecular mechanism of the pro-apoptotic activity of ASM controlled by oxidative stress to modulate the ER-mitochondrial bioenergetic metabolism, as well as suggests the disruption of CDK1-cyclin B1-mediated BCL-2/BCL-xL oncogenic activity by triggering oxidative stress-ASM-induced PI3K-Akt-GTP-Rac1 inactivation as a therapeutic approach for NPC.

UI MeSH Term Description Entries
D008297 Male Males
D008875 Middle Aged An adult aged 45 - 64 years. Middle Age
D008928 Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed) Mitochondrial Contraction,Mitochondrion,Contraction, Mitochondrial,Contractions, Mitochondrial,Mitochondrial Contractions
D004721 Endoplasmic Reticulum A system of cisternae in the CYTOPLASM of many cells. In places the endoplasmic reticulum is continuous with the plasma membrane (CELL MEMBRANE) or outer membrane of the nuclear envelope. If the outer surfaces of the endoplasmic reticulum membranes are coated with ribosomes, the endoplasmic reticulum is said to be rough-surfaced (ENDOPLASMIC RETICULUM, ROUGH); otherwise it is said to be smooth-surfaced (ENDOPLASMIC RETICULUM, SMOOTH). (King & Stansfield, A Dictionary of Genetics, 4th ed) Ergastoplasm,Reticulum, Endoplasmic
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077274 Nasopharyngeal Carcinoma A carcinoma that originates in the EPITHELIUM of the NASOPHARYNX and includes four subtypes: keratinizing squamous cell, non-keratinizing, basaloid squamous cell, and PAPILLARY ADENOCARCINOMA. It is most prevalent in Southeast Asian populations and is associated with EPSTEIN-BARR VIRUS INFECTIONS. Somatic mutations associated with this cancer have been identified in NPCR, BAP1, UBAP1, ERBB2, ERBB3, MLL2, PIK3CA, KRAS, NRAS, and ARID1A genes. Carcinoma, Nasopharyngeal,Carcinomas, Nasopharyngeal,Nasopharyngeal Carcinomas
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults
D016203 CDC2 Protein Kinase Phosphoprotein with protein kinase activity that functions in the G2/M phase transition of the CELL CYCLE. It is the catalytic subunit of the MATURATION-PROMOTING FACTOR and complexes with both CYCLIN A and CYCLIN B in mammalian cells. The maximal activity of cyclin-dependent kinase 1 is achieved when it is fully dephosphorylated. Cdk1 Protein Kinase,Cyclin-Dependent Kinase 1,Histone Kinase p34(cdc2),Protein p34cdc2,p34cdc2 Protein,cdc2+ Protein,cdk1 Kinase,Cyclin Dependent Kinase 1,Protein Kinase, CDC2,Protein Kinase, Cdk1,p34cdc2, Protein
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines

Related Publications

Jan-Gowth Chang, and Ni Tien, and Yi-Chih Chang, and Meng-Liang Lin, and Shih-Shun Chen
Cdk1/cyclin B1 controls Fas-mediated apoptosis by regulating caspase-8 activity.
December 2010, Molecular and cellular biology,
Jan-Gowth Chang, and Ni Tien, and Yi-Chih Chang, and Meng-Liang Lin, and Shih-Shun Chen
p21-Mediated nuclear retention of cyclin B1-Cdk1 in response to genotoxic stress.
September 2004, Molecular biology of the cell,
Jan-Gowth Chang, and Ni Tien, and Yi-Chih Chang, and Meng-Liang Lin, and Shih-Shun Chen
Triethylene glycol dimethacrylate impairs bioenergetic functions and induces oxidative stress in mitochondria via inhibiting respiratory Complex I.
July 2018, Dental materials : official publication of the Academy of Dental Materials,
Jan-Gowth Chang, and Ni Tien, and Yi-Chih Chang, and Meng-Liang Lin, and Shih-Shun Chen
Caveolin-1 impairs PKA-DRP1-mediated remodelling of ER-mitochondria communication during the early phase of ER stress.
July 2019, Cell death and differentiation,
Jan-Gowth Chang, and Ni Tien, and Yi-Chih Chang, and Meng-Liang Lin, and Shih-Shun Chen
Targeting E2F Sensitizes Prostate Cancer Cells to Drug-Induced Replication Stress by Promoting Unscheduled CDK1 Activity.
October 2022, Cancers,
Jan-Gowth Chang, and Ni Tien, and Yi-Chih Chang, and Meng-Liang Lin, and Shih-Shun Chen
Mitochondrial Ribosomal Protein L10 Associates with Cyclin B1/Cdk1 Activity and Mitochondrial Function.
November 2016, DNA and cell biology,
Jan-Gowth Chang, and Ni Tien, and Yi-Chih Chang, and Meng-Liang Lin, and Shih-Shun Chen
Phosphorylation of VP1 Mediated by CDK1-Cyclin B1 Facilitates Infectious Bursal Disease Virus Replication.
January 2023, Journal of virology,
Jan-Gowth Chang, and Ni Tien, and Yi-Chih Chang, and Meng-Liang Lin, and Shih-Shun Chen
Aflatoxin B1 impairs spermatogenesis: An experimental study for crosslink between oxidative stress and mitochondria-dependent apoptosis.
November 2018, Environmental toxicology,
Jan-Gowth Chang, and Ni Tien, and Yi-Chih Chang, and Meng-Liang Lin, and Shih-Shun Chen
Cyclin B1 and CDK1: nuclear localization and upstream regulators.
January 2003, Progress in cell cycle research,
Jan-Gowth Chang, and Ni Tien, and Yi-Chih Chang, and Meng-Liang Lin, and Shih-Shun Chen
CDK1-cyclin-B1-induced kindlin degradation drives focal adhesion disassembly at mitotic entry.
May 2022, Nature cell biology,
Copied contents to your clipboard!