Splice variants of lysosome‑associated membrane proteins 2A and 2B are involved in sunitinib resistance in human renal cell carcinoma cells

Abstract

Sunitinib, a tyrosine kinase inhibitor, is among the first-line treatments for metastatic or advanced stage renal cell carcinoma (RCC). However, patients with RCC develop resistance to sunitinib. We have previously demonstrated that lysosome-associated membrane protein 2 (LAMP-2), which has three splice variants with different functions (LAMP-2A, LAMP-2B, and LAMP-2C), is involved in RCC. In the present study, we examined which splice variants of LAMP-2 contributed to sunitinib resistance in RCC cells. In vitro analysis using ACHN, human RCC cell line, revealed that the IC 50 of sunitinib was significantly increased by overexpression of LAMP-2A and LAMP-2B, but not LAMP-2C (P<0.01). Kaplan-Meier survival analysis using clinical samples revealed an association between shorter survival and high expression of LAMP-2A and LAMP-2B, but not LAMP-2C, in patients with RCC treated with sunitinib (P=0.01). Furthermore, high expression of LAMP-2A and LAMP-2B in RCC revealed a weak to moderate inverse correlation with the tumor shrinkage rate and progression-free survival, respectively. Thus, high expression of LAMP-2A and LAMP-2B contributed to the acquisition of sunitinib resistance, indicating that the expression of these two variants can predict the efficacy of sunitinib treatment in patients with RCC.

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“…A survival analysis of RCC using clinical samples shows that RCC patients with higher expression of LAMP2A have a shorter progression-free survival [15], suggesting the negative regulation of CMA in the survival of RCC. A recent study reveals that CMA is activated in renal carcinoma cells and can promote the proliferation and invasion of renal carcinoma cells through pyruvate kinase isoform M2 (PKM2) in vitro [62], which plays a crucial role in cancer progression [88].…”

“…Sunitinib is a first-line drug for patients with metastatic advanced-stage RCC, but resistance to sunitinib is a severe threat to patient survival. In the RCC patients who received sunitinib for metastases followed by nephrectomy, the higher expression of LAMP2A suggests that LAMP2A-mediated CMA plays an important role in the resistance to sunitinib [15]. Therefore, CMA inhibitors might not only suppress proliferation and invasion of RCC, but also help overcome sunitinib resistance [15,62].…”

“…In the RCC patients who received sunitinib for metastases followed by nephrectomy, the higher expression of LAMP2A suggests that LAMP2A-mediated CMA plays an important role in the resistance to sunitinib [15]. Therefore, CMA inhibitors might not only suppress proliferation and invasion of RCC, but also help overcome sunitinib resistance [15,62]. In addition, the inhibition of PKM2 could also be a potential therapy target of RCC [62].…”

“…With the advances in the technique and molecular insights on CMA, more and more evidence on the role of CMA in distinct kidney diseases is emerging. It has been proven that CMA is involved in the progression of renal cancer and chemoresistance in renal cell carcinoma (RCC) patients [15]. Under the condition of oxidation, as with acute kidney injury (AKI), CMA is up-regulated to selectively degrade misfolded, oxidized, or damaged cytosolic proteins.…”

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

“…SU has been approved for treating gastrointestinal stromal tumors and advanced RCC [ 8 ]. As a first-line therapeutic drug for metastatic or advanced RCC, SU has significantly enhanced RCC prognosis among patients [ 9 ]. Nevertheless, resistance to SU has been recently reported, thus reducing RCC outcomes [ 10 ].…”