Abstract 4421: Intracellular cytomatrix actin and the Warburg effect

Abstract

Abstract Introduction: The cytoplasm of living cells is dynamic and the motion arising from fluctuating forces in cells is an active process, rather than being thermally induced. Motor proteins could be the primary causative force of intracellular movement. However, which motor protein is involved in the intracellular dynamics, what process requires fluctuational intracellular activity, and where the energy source comes from is unknown. To address the impact of intracellular motion in cellular processes, we chemically separated the viscous fluid (cytosol) and elastic solid (cytomatrix) phases of cytoplasm. The multiomic analysis was used to dissect the compositional differences between the liquid and solid phases. LC-MS/MS-based proteome analysis was used to identify the composition of the HCT-15 colon cancer cell cytomatrix. The mRNA translation was measured by Ribosome footprinting. Results: Since the kinesis of the solid phase can trigger liquid phase flux, the composition of the cytomatrix was the primary focus of the study of cytoplasmic motion. The systemic analysis of the cytomatrix constituency allowed the identification of a diverse functional group of proteomes that included cytoskeletal and structural elements of organoids, metabolic enzymes, and normal- and proto-oncogenic signaling pathways. The two-phase system elucidated how diverse chemical reactions can occur simultaneously within the cell cytoplasm. Namely, the immobilization of catalytic complexes on the solid cytomatrix physically segregates biochemical reactants, thereby overcoming spatial impediments and allowing diverse metabolic reactions to coincide. Actomyosin and other actin-binding proteins of cytomatrix were the most abundant and diverse proteome, indicating that the primary machinery driving cytomatrix mobility consists of actomyosin, actin-binding, and actin-regulating proteins of cytomatrix. The cytomatrix dynamics trigger the cytosolic motion that carries substrates to immobilized catalytic complexes of the cytomatrix, thereby increasing product output, which appears to be a more intense process in cancer cells due to genetic and epigenetic aberrations. Under normal physiological conditions, mitochondrial respiration can deliver the energy requirements of cytomatrix micromechanics, but in cancer cells, additional energy of ATP is supplied by the aerobic glycolysis known as the Warburg effect to provide the ATP surplus for actomyosin mechanics. Conclusion: The intracellular motion is supported through non-muscle actomyosin action of the solid phase (cytomatrix), permitting increased glycolytic pathway activity in tumor cells. This novel concept of cancer links the Warburg effect with the bioenergetics of cytomatrix micromechanics and the dynamics of metabolic processes in tumors. Thus, two of the mysteries in cancer cell biology, how chemical reactions occur in the cytoplasm and energy is generated by tumor cells, have now been linked. Citation Format: Tattym E. Shaiken. Intracellular cytomatrix actin and the Warburg effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4421.