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

Nishikawa,Ryoma; Osaki,Mitsuhiko; Sasaki,Ryo; Ishikawa,Mizuho; Yumioka,Tetsuya; Yamaguchi,Noriya; Iwamoto,Hideto; Honda,Masashi; Kabuta,Tomohiro; Takenaka,Atsushi; Okada,Futoshi

doi:10.3892/or.2020.7752

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

Authors:
- Ryoma Nishikawa
- Mitsuhiko Osaki
- Ryo Sasaki
- Mizuho Ishikawa
- Tetsuya Yumioka
- Noriya Yamaguchi
- Hideto Iwamoto
- Masashi Honda
- Tomohiro Kabuta
- Atsushi Takenaka
- Futoshi Okada
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Affiliations: Division of Urology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8503, Japan, Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8503, Japan, Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187‑8502, Japan
Published online on: September 4, 2020 https://doi.org/10.3892/or.2020.7752
Pages: 1810-1820
Copyright: © Nishikawa et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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 IC50 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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