miR-27-3p Enhances the Sensitivity of Triple-Negative Breast Cancer Cells to the Antitumor Agent Olaparib by Targeting PSEN-1, the Catalytic Subunit of Γ-Secretase

Abstract

Olaparib has been used in the treatment of triple-negative breast cancer (TNBC) with BRCA mutations. In the present study, we demonstrated the effect of miR-27-3p on the γ-secretase pathway by regulating the sensitivity of TNBC cells to olaparib. miR-27-3p, a microRNA with the potential to target PSEN-1, the catalytic subunit of γ-secretase mediating the second step of the cleavage of the Notch protein, was identified by the online tool miRDB and found to inhibit the expression of PSEN-1 by directly targeting the 3’-untranslated region (3’-UTR) of PSEN-1. The overexpression of miR-27-3p inhibited the activation of the Notch pathway via the inhibition of the cleavage of the Notch protein, mediated by γ-secretase, and, in turn, enhanced the sensitivity of TNBC cells to the antitumor agent olaparib. Transfection with PSEN-1 containing mutated targeting sites for miR-27-3p or the expression vector of the Notch protein intracellular domain (NICD) almost completely blocked the effect of miR-27-3p on the Notch pathway or the sensitivity of TNBC cells to olaparib, respectively. Therefore, our results suggest that the miR-27-3p/γ-secretase axis participates in the regulation of TNBC and that the overexpression of miR-27-3p represents a potential approach to enhancing the sensitivity of TNBC to olaparib.

Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

“…(2) epithelial-mesenchymal transition (80-82); (3) cancer stem cells (83)(84)(85); (4) PXR and other drug metabolism clearance mechanism (63); and (5) Notch pathway and other cell prosurvival and antiapoptotic mechanisms (38,(86)(87)(88). This research not only expands our molecular mechanism of HCC cell resistance to molecular targeted drugs but also helps to provide new strategies for HCC treatment.…”

“…Therefore, this study not only has scientific research value but also has great clinical value. The HCC cells may be resistant to molecular targeted drugs through a variety of mechanisms: (1) compensation between different signaling pathways ( 77 – 79 ); (2) epithelial–mesenchymal transition ( 80 – 82 ); (3) cancer stem cells ( 83 – 85 ); (4) PXR and other drug metabolism clearance mechanism ( 63 ); and (5) Notch pathway and other cell prosurvival and antiapoptotic mechanisms ( 38 , 86 – 88 ). This research not only expands our molecular mechanism of HCC cell resistance to molecular targeted drugs but also helps to provide new strategies for HCC treatment.…”

“…The hepatic cells (including the non-tumor cell line L-02, or the HCC cell lines HepG2, MHCC97-H, MHCC97-L, BEL-7402, SMMC-7721, or Hu7) were cultured and directly harvested for the Western blot experiments. Moreover, the subcutaneous tumor tissues were harvested and grinded with liquid nitrogen for the Western blot ( 37 , 38 ). Protein samples obtained from the cultured cells or the tumor tissues were analyzed by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) and trans-printed into polyvinylidene difluoride (PVDF) membranes.…”

A Novel Small Molecular Inhibitor of DNMT1 Enhances the Antitumor Effect of Radiofrequency Ablation in Lung Squamous Cell Carcinoma Cells

“…Given that the first cleavage step is mediated by ADAMs, including ADAM17 and ADAM10, pharmacological targeting of either could result in compensatory effects. However, because the second cleavage step is mediated by γ-secretase alone, pharmacological inhibition of this protein may be a promising approach to impede activation of the Notch signaling pathway, thus avoiding any compensatory effect between ADAM17 with ADAM10 ( Zhao et al, 2021 ). Therefore, γ-secretase may be a promising drug target for inhibiting the Notch pathway, and it may also improve the efficacy of antitumor therapy.…”

Novel Nanocrystal Injection of Insoluble Drug Anlotinib and Its Antitumor Effects on Hepatocellular Carcinoma

“…Anlotinib is usually administered to patients via the oral route (oral anlotinib hydrochloride capsule) (29). However, long treatment cycles (due to the limitations of anlotinib's own chemical properties) usually lead to multi-drug resistance (MDR) of the cancer cells (30)(31)(32). Special equipment for nanocrystal preparation can be used to disperse the insoluble drug particles that are coarsely scattered in water into sub-nano dispersions of drug particles smaller than 500 nm without changing the original crystal structure of the drug-delivering system (33)(34)(35)(36).…”