Sunitinib treatment promotes metastasis of drug-resistant renal cell carcinoma via TFE3 signaling pathway

Abstract

Receptor tyrosine kinase (RTK) inhibitors, such as sunitinib and sorafenib, remain the first-line drugs for the treatment of mRCC. Acquired drug resistance and metastasis are the main causes of treatment failure. However, in the case of metastasis Renal Cell Cancer (mRCC), which showed a good response to sunitinib, we found that long-term treatment with sunitinib could promote lysosome biosynthesis and exocytosis, thereby triggering the metastasis of RCC. By constructing sunitinib-resistant cell lines in vivo, we confirmed that TFE3 plays a key role in the acquired resistance to sunitinib in RCC. Under the stimulation of sunitinib, TFE3 continued to enter the nucleus, promoting the expression of endoplasmic reticulum (ER) protein E-Syt1. E-Syt1 and the lysosomal membrane protein Syt7 form a heterodimer, which induces ER fragmentation, Ca2+ release, and lysosomal exocytosis. Lysosomal exocytosis has two functions: pumping sunitinib out from the cytoplasm, which promotes resistance to sunitinib in RCC, releasing cathepsin B (CTSB) into the extracellular matrix (ECM), which can degrade the ECM to enhance the invasion and metastasis ability of RCC. Our study found that although sunitinib is an effective drug for the treatment of mRCC, once RCC has acquired resistance to sunitinib, sunitinib treatment will promote metastasis.

Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells

“…In particular, anchoring proteins, i.e., collagen, fibronectin, and laminin, connecting cells with the extracellular matrix or the microenvironment were downregulated ( Figure 2 and Supplementary Table S2 ). The downregulation of extracellular matrix receptors and cell adhesion pathways were reported by Li et alby proteomic analysis after 4 years of treatment with sunitinib [ 59 ]. Furthermore, the production of cell plasma components, signaling, and lysosomal function appeared to be affected ( Figure 3 ).…”

Biliverdin/Bilirubin Redox Pair Protects Lens Epithelial Cells against Oxidative Stress in Age-Related Cataract by Regulating NF-κB/iNOS and Nrf2/HO-1 Pathways

“…The procedures were determined as reported elsewhere using nuclear extraction kit (ab113474; Abcam, Shanghai, China) [ 47 ]. Briefly, cell samples were washed in ice-cold phosphate-buffered saline and centrifuged for 5 min at 1,000 rpm.…”

Circular RNA Eps15-homology domain-containing protein 2 induce resistance of renal cell carcinoma to sunitinib via microRNA-4731-5p/ABCF2 axis

“…However, patients later develop resistance to this treatment. Additionally, the long-term application of SU therapy elevates lysosomal biosynthesis and exocytosis, thus triggering metastasis of RCC [ 23 ]. Consequently, further understanding of RCC pathogenesis and the molecular mechanism of resistance to SU could help develop new biomarkers to prevent SU resistance.…”