Modulating the Siah2-PHD3-HIF1α axis and/or autophagy potentially retard colon cancer proliferation possibly, due to the damping of colon cancer stem cells - 10/09/22
, Samar Elsebaey a , Shady Allam b , Alaa El-Sisi c 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
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Colon cancer is solid tumor that associated with hypoxia. |
• | HIF-1α induces autophagy to provide nutrients and energy for tumor growth. |
• | Hypoxia and Autophagy are important regulators of cancer stem cells growth. |
• | Vitk3 regulates colon cancer growth by targeting Siah2-PHD3-HIF-1α axis. |
• | Autophagy inhibitor and Vitk3 may be a promising approach in reducing colon CSCs growth. |
Abbreviations : AED, BSA, CA19.9, CMC, CSCs, DAB, DMH, EpCAM, GSH, HCQ, HIF-1α, LC3Ⅰ, MDA, MMP-9, PHDs, PVDF, ROS, SCF, Siah2, SV, TBST, VEGF, Vitk3
Keywords : Colon cancer, Hypoxia, Autophagy, Vitamin K3, Hydroxychloroquine, CSCs
Plan
Vol 154
Article 113562- octobre 2022 Retour au numéro
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