Full Text | PDF

Share on tweeters Share on facebook Share on linkedin Share on googleplus

Theranostics 2022; 12(18):7681-7698. doi:10.7150/thno.74974 This issue Cite

Research Paper

AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy

Changqing Wu3*, Chaoliu Dai4*, Xinyu Li1,2*, Mingju Sun3, Hongwei Chu3, Qiuhui Xuan3, Yalei Yin3, Chengnan Fang3, Fan Yang1, Zhonghao Jiang4, Qing Lv1,2, Keqing He2, Yiying Qu1,2, Baofeng Zhao3, Ke Cai5, Shuijun Zhang6, Ran Sun7, Guowang Xu3, Lihua Zhang3, Siyu Sun1✉, Yang Liu1,2,3✉

1. Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
2. Innovative Research Center for Integrated Cancer Omics, Shengjing Hospital of China Medical University, Shenyang 110004, China.
3. (CAS) Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
4. Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.
5. School of Life Science, Dalian University, Dalian 116023, China.
6. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
7. National Engineering Laboratory for Internet Medical System and Application, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
* These authors contributed equally to this work.

✉ Corresponding authors: Siyu Sun, M.D. Ph.D. Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, China. 36 Sanhao St. Shenyang, 110004, China; Tel: 86-24-23392617; Fax: 86-24-23392617; Email: sunsyorg. Yang Liu, Ph.D. Department of Gastroenterology, Innovative Research Center for Integrated Cancer Omics, Shengjing Hospital of China Medical University. 36 Sanhao St. Shenyang, 110004, China; Tel: 86-24-88483780; Fax: 86-24-88483780; Email: yliuqq1980com. More

Citation:
Wu C, Dai C, Li X, Sun M, Chu H, Xuan Q, Yin Y, Fang C, Yang F, Jiang Z, Lv Q, He K, Qu Y, Zhao B, Cai K, Zhang S, Sun R, Xu G, Zhang L, Sun S, Liu Y. AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy. Theranostics 2022; 12(18):7681-7698. doi:10.7150/thno.74974. https://www.thno.org/v12p7681.htm
Other styles

File import instruction

Abstract

Graphic abstract

Rationale: Increased lipid droplet (LD) formation has been linked to tumor metastasis, stemness, and chemoresistance in various types of cancer. Here, we revealed that LD formation is critical for the adaptation to sorafenib in hepatocellular carcinoma (HCC) cells. We aim to investigate the LD function and its regulatory mechanisms in HCC.

Methods: The key proteins responsible for LD formation were screened by both metabolomics and proteomics in sorafenib-resistant HCC cells and further validated by immunoblotting and immunofluorescence staining. Biological function of AKR1C3 was evaluated by CRISPR/Cas9-based gene editing. Isotopic tracing analysis with deuterium3-labeled palmitate or carbon13-labeled glucose was conducted to investigate fatty acid (FA) and glucose carbon flux. Seahorse analysis was performed to assess the glycolytic flux and mitochondrial function. Selective AKR1C3 inhibitors were used to evaluate the effect of AKR1C3 inhibition on HCC tumor growth and induction of autophagy.

Results: We found that long-term sorafenib treatment impairs fatty acid oxidation (FAO), leading to LD accumulation in HCC cells. Using multi-omics analysis in cultured HCC cells, we identified that aldo-keto reductase AKR1C3 is responsible for LD accumulation in HCC. Genetic loss of AKR1C3 fully depletes LD contents, navigating FA flux to phospholipids, sphingolipids, and mitochondria. Furthermore, we found that AKR1C3-dependent LD accumulation is required for mitigating sorafenib-induced mitochondrial lipotoxicity and dysfunction. Pharmacologic inhibition of AKR1C3 activity instantly induces autophagy-dependent LD catabolism, resulting in mitochondrial fission and apoptosis in sorafenib-resistant HCC clones. Notably, manipulation of AKR1C3 expression is sufficient to drive the metabolic switch between FAO and glycolysis.

Conclusions: Our findings revealed that AKR1C3-dependent LD formation is critical for the adaptation to sorafenib in HCC through regulating lipid and energy homeostasis. AKR1C3-dependent LD accumulation protects HCC cells from sorafenib-induced mitochondrial lipotoxicity by regulating lipophagy. Targeting AKR1C3 might be a promising therapeutic strategy for HCC tumors.

Keywords: Lipid homeostasis, Lipid droplets, Lipophagy, Metabolic reprogramming, Mitochondrial dysfunction.

Citation styles

APA
Wu, C., Dai, C., Li, X., Sun, M., Chu, H., Xuan, Q., Yin, Y., Fang, C., Yang, F., Jiang, Z., Lv, Q., He, K., Qu, Y., Zhao, B., Cai, K., Zhang, S., Sun, R., Xu, G., Zhang, L., Sun, S., Liu, Y. (2022). AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy. Theranostics, 12(18), 7681-7698. https://doi.org/10.7150/thno.74974.

ACS
Wu, C.; Dai, C.; Li, X.; Sun, M.; Chu, H.; Xuan, Q.; Yin, Y.; Fang, C.; Yang, F.; Jiang, Z.; Lv, Q.; He, K.; Qu, Y.; Zhao, B.; Cai, K.; Zhang, S.; Sun, R.; Xu, G.; Zhang, L.; Sun, S.; Liu, Y. AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy. Theranostics 2022, 12 (18), 7681-7698. DOI: 10.7150/thno.74974.

NLM
Wu C, Dai C, Li X, Sun M, Chu H, Xuan Q, Yin Y, Fang C, Yang F, Jiang Z, Lv Q, He K, Qu Y, Zhao B, Cai K, Zhang S, Sun R, Xu G, Zhang L, Sun S, Liu Y. AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy. Theranostics 2022; 12(18):7681-7698. doi:10.7150/thno.74974. https://www.thno.org/v12p7681.htm

CSE
Wu C, Dai C, Li X, Sun M, Chu H, Xuan Q, Yin Y, Fang C, Yang F, Jiang Z, Lv Q, He K, Qu Y, Zhao B, Cai K, Zhang S, Sun R, Xu G, Zhang L, Sun S, Liu Y. 2022. AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy. Theranostics. 12(18):7681-7698.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image

©2024 Ivyspring International Publisher. Terms of use