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Article

Combining Everolimus and Ku0063794 Promotes Apoptosis of Hepatocellular Carcinoma Cells via Reduced Autophagy Resulting from Diminished Expression of miR-4790-3p

1
Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
2
Department of Surgery, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Korea
3
Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
4
Department of Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 11765, Korea
*
Author to whom correspondence should be addressed.
Academic Editor: Janusz Blasiak
Int. J. Mol. Sci. 2021, 22(6), 2859; https://doi.org/10.3390/ijms22062859
Received: 14 December 2020 / Revised: 9 March 2021 / Accepted: 9 March 2021 / Published: 11 March 2021
(This article belongs to the Section Molecular Genetics and Genomics)
It is challenging to overcome the low response rate of everolimus in the treatment of patients with hepatocellular carcinoma (HCC). To overcome this challenge, we combined everolimus with Ku0063794, the inhibitor of mTORC1 and mTORC2, to achieve higher anticancer effects. However, the precise mechanism for the synergistic effects is not clearly understood yet. To achieve this aim, the miRNAs were selected that showed the most significant variation in expression according to the mono- and combination therapy of everolimus and Ku0063794. Subsequently, the roles of specific miRNAs were determined in the processes of the treatment modalities. Compared to individual monotherapies, the combination therapy significantly reduced viability, increased apoptosis, and reduced autophagy in HepG2 cells. The combination therapy led to significantly lower expression of miR-4790-3p and higher expression of zinc finger protein225 (ZNF225)—the predicted target of miR-4790-3p. The functional study of miR-4790-3p and ZNF225 revealed that regarding autophagy, miR-4790-3p promoted it, while ZNF225 inhibited it. In addition, regarding apoptosis, miR-4790-3p inhibited it, while ZNF225 promoted it. It was also found that HCC tissues were characterized by higher expression of miR-4790-3p and lower expression of ZNF225; HCC tissues were also characterized by higher autophagic flux. We, thus, conclude that the potentiated anticancer effect of the everolimus and Ku0063794 combination therapy is strongly associated with reduced autophagy resulting from diminished expression of miR-4790-3p, as well as higher expression of ZNF225. View Full-Text
Keywords: autophagy; hepatocellular carcinoma; miR-4790-3p; mTOR inhibitor; ZNF225 autophagy; hepatocellular carcinoma; miR-4790-3p; mTOR inhibitor; ZNF225
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MDPI and ACS Style

Choi, H.J.; Park, J.H.; Kim, O.-H.; Kim, K.-H.; Hong, H.E.; Seo, H.; Kim, S.-J. Combining Everolimus and Ku0063794 Promotes Apoptosis of Hepatocellular Carcinoma Cells via Reduced Autophagy Resulting from Diminished Expression of miR-4790-3p. Int. J. Mol. Sci. 2021, 22, 2859. https://doi.org/10.3390/ijms22062859

AMA Style

Choi HJ, Park JH, Kim O-H, Kim K-H, Hong HE, Seo H, Kim S-J. Combining Everolimus and Ku0063794 Promotes Apoptosis of Hepatocellular Carcinoma Cells via Reduced Autophagy Resulting from Diminished Expression of miR-4790-3p. International Journal of Molecular Sciences. 2021; 22(6):2859. https://doi.org/10.3390/ijms22062859

Chicago/Turabian Style

Choi, Ho J., Jung H. Park, Ok-Hee Kim, Kee-Hwan Kim, Ha E. Hong, Haeyeon Seo, and Say-June Kim. 2021. "Combining Everolimus and Ku0063794 Promotes Apoptosis of Hepatocellular Carcinoma Cells via Reduced Autophagy Resulting from Diminished Expression of miR-4790-3p" International Journal of Molecular Sciences 22, no. 6: 2859. https://doi.org/10.3390/ijms22062859

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