Nrf2/p‑Fyn/ABCB1 axis accompanied by p‑Fyn nuclear accumulation plays pivotal roles in vinorelbine resistance in non‑small cell lung cancer

Tamari,Shigeyuki; Menju,Toshi; Toyazaki,Toshiya; Miyamoto,Hideaki; Chiba,Naohisa; Noguchi,Misa; Ishikawa,Hiroyuki; Miyata,Ryo; Kayawake,Hidenao; Tanaka,Satona; Yamada,Yoshito; Yutaka,Yojiro; Nakajima,Daisuke; Ohsumi,Akihiro; Hamaji,Masatsugu; Date,Hiroshi

doi:10.3892/or.2022.8386

Nrf2/p‑Fyn/ABCB1 axis accompanied by p‑Fyn nuclear accumulation plays pivotal roles in vinorelbine resistance in non‑small cell lung cancer

Authors:
- Shigeyuki Tamari
- Toshi Menju
- Toshiya Toyazaki
- Hideaki Miyamoto
- Naohisa Chiba
- Misa Noguchi
- Hiroyuki Ishikawa
- Ryo Miyata
- Hidenao Kayawake
- Satona Tanaka
- Yoshito Yamada
- Yojiro Yutaka
- Daisuke Nakajima
- Akihiro Ohsumi
- Masatsugu Hamaji
- Hiroshi Date
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Affiliations: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606‑8507, Japan
Published online on: August 12, 2022 https://doi.org/10.3892/or.2022.8386
Article Number: 171

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Abstract

Adjuvant cisplatin‑vinorelbine is a standard therapy for stage II/III lung cancer. However, a poor survival rate of patients with lung cancer is attributed to vinorelbine resistance arising from ATP‑binding cassette (ABC) sub‑family B member 1 (ABCB1) and phosphorylated Fyn (p‑Fyn) overexpression. However, the underlying mechanisms remain unclear. NF‑E2‑related factor 2 (Nrf2) regulates the ABC family and activates the nuclear transport of Fyn. The present study evaluated the roles of the Nrf2/p‑Fyn/ABCB1 axis in vinorelbine‑resistant (VR) cells and clinical samples. To establish VR cells, H1299 cells were exposed to vinorelbine, and the intracellular reactive oxygen species (ROS) level in the H1299 cells was determined using a DCFH‑DA assay. The total and subcellular expression of Nrf2, ABCB1 and p‑Fyn in VR cells was evaluated. Immunofluorescence was used to detect the subcellular localization of p‑Fyn in VR cells. A cell viability assay was used to examine whether the sensitivity of VR cells to vinorelbine is dependent on Nrf2 activity. Immunohistochemistry was performed on 104 tissue samples from patients with lung cancer who underwent surgery followed by cisplatin‑vinorelbine treatment. The results revealed that persistent exposure to vinorelbine induced intracellular ROS formation in H1299 cells. p‑Fyn was localized in the nucleus, and ABCB1 and Nrf2 were overexpressed in VR cells. ABCB1 expression was dependent on Nrf2 downstream activation. The decreased expression of Nrf2 restored the sensitivity of VR cells to vinorelbine. In the surgical samples, Nrf2 and ABCB1 were associated with disease‑free survival, and p‑Fyn was associated with overall survival (P<0.05). On the whole, the present study demonstrates that Nrf2 upregulates ABCB1 and, accompanied by the nuclear accumulation of p‑Fyn, induces vinorelbine resistance. These findings may facilitate the development of drug resistance prevention strategies or new drug targets against non‑small cell lung cancer.

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