Modulating the Siah2-PHD3-HIF1α axis and/or autophagy potentially retard colon cancer proliferation possibly, due to the damping of colon cancer stem cells.

Abstract

BACKGROUND:

Hypoxic microenvironment of colon cancer is associated with HIF-1α upregulation. HIF-1α response elements are responsible for autophagy induction that promotes tumor proliferation. Moreover, HIF-1α induces tumor cell proliferation via maintaining cancer stem cells (CSCs) survival. Siah2 is E3 ubiquitin ligase that indirectly stabilizes HIF-1α. We hypothesized that dual inhibition of Siah2 as well as autophagy could be a promising approach that may inhibit CSCs growth.

AIM OF THE WORK:

This study investigated the possible effect of vitamin K3 as a Siah2 inhibitor and hydroxychloroquine as an autophagy inhibitor in colon cancer management. The effect (if any) of these agents on CSCs growth will be also manipulated.

METHODS:

Colon cancer was induced by dimethylhydrazine. MDA and GSH were selected as oxidative stress markers, Expression of HIF-1α, Caspase-3, VEGF, MMP-9, EpCAM, SCF, and CA19.9 were assayed using immunoassay. The Western blot technique was used to assess LC3Ⅰ, CD44, and CD133 whereas RT-PCR was used to investigate PHD3 and CD44 in colon tissues. Additionally, Ki-67 and Siah2 were detected immunohistochemically.

RESULTS:

vitamin K3 and hydroxychloroquine either alone or in combination downregulated the expression of Siah2 and HIF-1α through upregulating PHD3 in colon tissues. This combination significantly downregulated MDA, Ki-67, VEGF, and MMP-9 expression and upregulated the expression of GSH and caspase-3. LC3Ⅰ was also upregulated. Interestingly, these therapeutic options were correlated with down-regulation of the cancer stem cell marker such as CD44 and EpCAM.

CONCLUSION:

Our results suggested that suppression of both Siah2-PHD3-HIF-1α axis and autophagy retard colon cancer proliferation and dampened CSCs.

• Authors: Sherin Zakaria, Samar Elsebaey, Shady Allam, Alaa El-Sisi
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 154 Pg. 113562 (Oct 2022) ISSN: 1950-6007 [Electronic] France
• PMID: 35994813 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Epithelial Cell Adhesion Molecule
• Hypoxia-Inducible Factor 1, alpha Subunit
• Ki-67 Antigen
• Vascular Endothelial Growth Factor A
• Hydroxychloroquine
• Vitamin K 3
• Ubiquitin-Protein Ligases
• Caspase 3
• Matrix Metalloproteinase 9

Topics

• Autophagy
• Caspase 3 (metabolism)
• Cell Hypoxia (physiology)
• Cell Proliferation
• Colonic Neoplasms (drug therapy)
• Epithelial Cell Adhesion Molecule
• Humans
• Hydroxychloroquine
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Ki-67 Antigen (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Neoplastic Stem Cells (metabolism)
• Tumor Microenvironment
• Ubiquitin-Protein Ligases (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)
• Vitamin K 3