2. Academic Validation
  3. Cell-free ascites from ovarian cancer patients induces Warburg metabolism and cell proliferation through TGFβ-ERK signaling

Cell-free ascites from ovarian cancer patients induces Warburg metabolism and cell proliferation through TGFβ-ERK signaling

  • Geroscience. 2024 Jan 10. doi: 10.1007/s11357-023-01056-1.
Dóra Szeőcs 1 2,  Beáta Vida 3,  Gábor Petővári 4,  Szilárd Póliska 5,  Eszter Janka 6,  Adrienn Sipos 1 2 7,  Karen Uray 1 2,  Anna Sebestyén 4,  Zoárd Krasznai 3,  Péter Bai 8 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary, 4032.
  • 2 Center of Excellence, The Hungarian Academy of Sciences, Debrecen, Hungary.
  • 3 Department of Obstetrics and Gynecology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary, 4032.
  • 4 Department of Pathology, Semmelweis University, Budapest, Hungary.
  • 5 Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary, 4032.
  • 6 Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary, 4032.
  • 7 HUN-REN-DE Cell Biology and Signaling Research Group, Debrecen, Hungary, 4032.
  • 8 Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary, 4032. [email protected].
  • 9 Center of Excellence, The Hungarian Academy of Sciences, Debrecen, Hungary. [email protected].
  • 10 HUN-REN-DE Cell Biology and Signaling Research Group, Debrecen, Hungary, 4032. [email protected].
  • 11 MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, Hungary, 4032. [email protected].
  • 12 Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary, 4032. [email protected].
PMID: 38196068 DOI: 10.1007/s11357-023-01056-1
Abstract

Ascites plays a key role in supporting the metastatic potential of ovarian Cancer cells. Shear stress and carry-over of Cancer cells by ascites flow support carcinogenesis and metastasis formation. In addition, soluble factors may participate in the procarcinogenic effects of ascites in ovarian Cancer. This study aimed to determine the biological effects of cell-free ascites on carcinogenesis in ovarian Cancer cells. Cell-free ascites from ovarian Cancer patients (ASC) non-selectively induced cell proliferation in multiple models of ovarian Cancer and untransformed primary human dermal fibroblasts. Furthermore, ASC induced a Warburg-type rearrangement of cellular metabolism in A2780 ovarian Cancer cells characterized by increases in cellular oxygen consumption and glycolytic flux; increases in glycolytic flux were dominant. ASC induced mitochondrial uncoupling and fundamentally reduced fatty acid oxidation. Ascites-elicited effects were uniform among ascites specimens. ASC-elicited transcriptomic changes in A2780 ovarian Cancer cells included induction of the TGFβ-ERK/MEK pathway, which plays a key role in inducing cell proliferation and oncometabolism. ASC-induced gene expression changes, as well as the overexpression of members of the TGFβ signaling system, were associated with poor survival in ovarian Cancer patients. We provided evidence that the activation of the autocrine/paracrine of TGFβ signaling system may be present in bladder urothelial carcinoma and stomach adenocarcinoma. Database analysis suggests that the TGFβ system may feed forward bladder urothelial carcinoma and stomach adenocarcinoma. Soluble components of ASC support the progression of ovarian Cancer. These results suggest that reducing ascites production may play an essential role in the treatment of ovarian Cancer by inhibiting the progression and reducing the severity of the disease.

Keywords

Ascites; Coupled respiration; Fatty acid oxidation; Glucose oxidation; Ovarian cancer; Proliferation; Tumor microenvironment; Warburg metabolism.

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