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

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 deuterium 3 -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.

Prognostic signatures of sphingolipids: Understanding the immune landscape and predictive role in immunotherapy response and outcomes of hepatocellular carcinoma

“…As a result, we aimed to confirm whether inhibiting SMPD2 or CSTA enhances the sensitivity of liver cancer cells to lapatinib (Figure 11B). Additionally, it is worth noting that SMPD2 is mainly located on lipid droplets and plasma membranes (Figure 8B), and lipid droplet formation is known to confer resistance of HCC cells to chemotherapy (43). This may partly explain why lapatinib increases the sensitivity of HCC cells to SMPD2 inhibition.…”

“…Alterations in the levels of certain genes involved in sphingolipid metabolism may have a significant impact on the effectiveness of chemotherapy (42,43). Using gene expression data from different risk subgroups, we utilized the pRRophetic package to predict variations in the sensitivity to clinical antitumor drugs across different risk groups (Supplementary Table S2; Figure 10).…”

Cullin‐associated and neddylation‐dissociated 1 regulate reprogramming of lipid metabolism through SKP1‐Cullin‐1‐F‐boxFBXO11‐mediated heterogeneous nuclear ribonucleoprotein A2/B1 ubiquitination and promote hepatocellular carcinoma

“…Lipids are reported to be an important energy source to fuel tumour progression and metastasis 7 . In addition, studies have confirmed lipid droplets (LDs) and lipogenesis play an important role in the development and stemness of HCC 8–11 …”

“…7 In addition, studies have confirmed lipid droplets (LDs) and lipogenesis play an important role in the development and stemness of HCC. [8][9][10][11] SKP-Cullin1-F-box (SCF) complexes have been suggested to play important roles in multiple processes including adipogenesis and lipogenesis. 12,13 The typical biological function of the SCF complex is to induce the degradation of various substrates through ubiquitination.…”

Glycerol‐3‐phosphate acyltransferase 3‐mediated lipid droplets accumulation confers chemoresistance of colorectal cancer

“…In CRC cells, LDs are crucial players in tumorigenicity and development 10 . They were also reported to participate in resistance to drug therapy 11 . Chemotherapeutics treatment significantly increased LD content 12 .…”