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High Expression of the Mitophagy-Related Protein Pink1 is Associated with a Poor Response to Chemotherapy and a Poor Prognosis for Patients Treated with Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Autophagy plays a major role in cellular homeostasis and is implicated in cancer progression. Damaged mitochondria are scavenged and eliminated by mitochondrial autophagy, referred to as mitophagy, which can promote cancer cell survival. This study investigated the expression and effects of the autophagy-related protein LC3 and the mitophagy-related protein Pink1 in human esophageal squamous cell carcinoma (ESCC).

Methods

Both LC3 and Pink1 were analyzed by immunohistochemistry in tissues from 217 ESCC patients, including 159 patients undergoing neoadjuvant chemotherapy. The relationships between LC3 and Pink1 expression and various clinicopathologic factors were determined. In vitro assays were performed to assess the role of LC3 and Pink1 in ESCC chemoresistance.

Results

High LC3 expression was observed in 47.9% and high Pink1 expression in 48.4% of the ESCC patients. Pink1 expression was significantly higher in patients who underwent chemotherapy than in patients who did not (p = 0.032). High LC3 and Pink1 expression was significantly correlated with poor response to chemotherapy (p = 0.004 and p < 0.001, respectively), and high expression of Pink1, but not LC3, was significantly correlated with a poor prognosis for patients treated with preoperative chemotherapy (p = 0.007). Multivariate analysis identified Pink1 expression as an independent prognostic factor (p = 0.042). In vitro assays demonstrated that LC3-II and Pink1 expression increased after chemotherapeutic treatment in the ESCC cell line, and inhibition of autophagy and mitophagy using chloroquine and siPink1, respectively, restored chemosensitivity.

Conclusions

High expression of Pink1 is associated with chemoresistance and a poor prognosis for ESCC patients undergoing neoadjuvant chemotherapy.

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Disclosure

There are no conflicts of interest.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

    Kotaro Yamashita MD, Hiroshi Miyata MD, FACS, PhD, Tomoki Makino MD, Yasunori Masuike MD, Haruna Furukawa MD, Koji Tanaka MD, Yasuhiro Miyazaki MD, Tsuyoshi Takahashi MD, Yukinori Kurokawa MD, FACS, Makoto Yamasaki MD, Kiyokazu Nakajima MD, FACS, Shuji Takiguchi MD, Masaki Mori MD, FACS & Yuichiro Doki MD

  2. Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka, Japan

    Hiroshi Miyata MD, FACS, PhD

  3. Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan

    Eiichi Morii MD

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  1. Kotaro Yamashita MD
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  2. Hiroshi Miyata MD, FACS, PhD
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  14. Masaki Mori MD, FACS
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Corresponding author

Correspondence to Hiroshi Miyata MD, FACS, PhD.

Electronic supplementary material

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Supplementary material 1 (DOCX 29 kb)

Supplementary material 2 (DOCX 18 kb)

10434_2017_6096_MOESM3_ESM.tif

Fig. S1 Correlation between LC3 and Pink1 expression and prognosis for esophageal squamous cell carcinoma (ESCC) patients. Overall survival according to (A) LC3 and (B) Pink1 expression in 217 ESCC patients with and without preoperative chemotherapy is shown. Supplementary material 3 (TIFF 1486 kb)

10434_2017_6096_MOESM4_ESM.tif

Fig. S2 Induction of LC3 by chemotherapeutic treatment in esophageal squamous cell carcinoma (ESCC) cells. A Western blot analysis of Pink1 and LC3 in ESCC cells after cisplatin exposure. TE11 cells were treated with cisplatin for 1, 2, 4, 8, or 12 h. B Western blot analysis of Pink1 and LC3 in ESCC cells after cisplatin exposure. TE11 cells were treated with 1.0, 2.0, 4.0, 8.0, or 16.0 µmol of cisplatin for 24 h. LC3 and Pink1 expression was measured using Western blot analyses. Supplementary material 4 (TIFF 107 kb)

10434_2017_6096_MOESM5_ESM.tif

Fig. S3 Immunofluorecent staining of LC3 in esophageal squamous cell carcinoma (ESCC) cells under the chemotherapeutic treatment. TE11 cells were treated with 8 µmol of cisplatin for 24 h. Cells were visualized using a confocal laser microscope (BZ-X710 microscope; objective × 200). Red dots correspond with accumulated LC3 in autophagosomes, and nuclei were stained with Hoechst 33342 (blue). Supplementary material 5 (TIFF 474 kb)

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Yamashita, K., Miyata, H., Makino, T. et al. High Expression of the Mitophagy-Related Protein Pink1 is Associated with a Poor Response to Chemotherapy and a Poor Prognosis for Patients Treated with Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 24, 4025–4032 (2017). https://doi.org/10.1245/s10434-017-6096-8

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  • DOI: https://doi.org/10.1245/s10434-017-6096-8

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