STAT2/SLC27A3/PINK1-mediated mitophagy remodeling lipid metabolism contributes to pazopanib resistance in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is a common type of cancer in the urinary system. Currently, the first-line treatments for advanced or metastatic ccRCC are tyrosine kinase inhibitors (TKIs); however, patients often develop resistance to these therapies.

Are there key genes involved in TKI resistance in ccRCC? What mechanisms are associated with this development? A research team, led by Professor Ben Liu from the Department of Urology at the First Affiliated Hospital of Zhejiang University School of Medicine, has conducted in-depth research on this topic.

Both lipid metabolic reprogramming and mitophagy are linked to tumor acquired drug resistance, while solute carrier family 27 member 3 (SLC27A3), which is significantly elevated in lipid-rich tumors like ccRCC, is associated with ccRCC poor prognosis, Professor Liu Ben noted. However, the upstream regulatory mechanisms of SLC27A3 and its impact on mitophagy and lipid reprogramming in ccRCC, as well as its role in TKI resistance, have yet to be explored.

The study was published on November 26, 2024 in the journal Research, the first Science Partner Journal recently launched by the American Association for the Advancement of Science (AAAS) in collaboration with the China Association for Science and Technology (CAST). Liu is a professor of urological tumor in the First Affiliated Hospital of Zhejiang University School of Medicine.

This study used various experimental detection techniques. The genes related to lipid metabolism were screened by mRNA sequencing. Lipid droplets (LDs) were detected by Red Oil O and BODIPY probe. Micro-targeted lipidomic of acyl-CoA and lipid metabolomics was used to screen potential metabolites of SLC27A3. The mitochondrial membrane potential (MMP) and Reactive Oxygen Species (ROS) levels were detected by JC-1 and DCF probes, among others.

"We found that SLC27A3 was upregulated in pazopanib resistant ccRCC, and its high expression was associated with lipid metabolism and indicated poor prognosis," pointed out Professor Liu. “GO and KEGG pathway analysis from RNA sequencing showed that PINK1/Parkin-mediated mitophagy pathway was enriched in 786-O-PR. Silencing SLC27A3 significantly reduced the accumulation of LD and suppressed mitophagy, thereby overcoming pazopanib resistance both in vitro and in vivo.”

Moreover, SLC27A3 functions as an acyl-CoA ligase catalyzing the formation of acyl-CoA, which refers to fatty acid oxidation and synthesis of lipid. Over-produced acyl-CoA oxidation in mitochondria resulted in MMP decrease and ROS production, triggering PINK1/Parkin-mediated mitophagy. Moreover, mitophagy inhibition led to more ROS accumulation, indicating that mitophagy can keep ROS at an appropriate level by negative feedback. Mitophagy, simultaneously, prevented fatty acid oxidation by consuming CPT1a in mitochondria, forcing synthesis of lipid stored in LDs by transforming acyl-CoA, to support ccRCC progression. Besides, STAT2 was identified as a core component of a potential upstream transcription factor complex for SLC27A3.

Professor Liu explained, “We have discovered that SLC27A3 is involved in ccRCC TKI resistance, which may lead to new treatment options for ccRCC.”