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ACAT-1-Regulated Cholesteryl Ester Accumulation Modulates Gemcitabine Resistance in Biliary Tract Cancer

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

Abstract

Background

Biliary tract cancer (BTC) has few choices of chemotherapy, including gemcitabine, therefore exploring the mechanisms of gemcitabine resistance is important. We focused on lipid metabolism because biliary tract epithelial cells are essential in cholesterol and bile acid metabolism and the messenger RNA (mRNA) microarray analysis showed high acyl coenzyme A: cholesterol acyltransferase 1 (ACAT-1) expression in BTC gemcitabine-resistant (GR) cell lines. We hypothesized that aberrant accumulation of cholesteryl ester (CE) regulated by ACAT-1 could modulate GR in BTC.

Methods

CE accumulations were measured in human BTC cell lines, and the relationships between CE levels, ACAT-1 expressions, and gemcitabine sensitivity were analyzed. We performed a small-interfering RNA (siRNA)-mediated knockdown and biochemical inhibition of ACAT-1 in BTC cell lines and alterations of gemcitabine sensitivity were evaluated. To evaluate the clinical significance of ACAT-1 in regard to GR, immunohistochemistry was performed and ACAT-1 expressions were analyzed in resected BTC specimens.

Results

CE levels were correlated with ACAT-1 expressions and GR in four human BTC cell lines. siRNA-mediated knockdown of ACAT-1 in two independent GR cell clones as well as ACAT-1 inhibitor treatment significantly increased gemcitabine sensitivity; knockdown of ACAT-1: 5.63- and 8.02-fold; ACAT-1 inhibitor: 8.75- and 9.13-fold, respectively. ACAT-1 expression in resected BTC specimens revealed that the disease-free survival of the ACAT-1 low-intensity group (median 2.3 years) had a significantly better outcome than that of the ACAT-1 high-intensity group (median 1.1 years) under gemcitabine treatment after surgery (*p < 0.05).

Conclusions

Our findings suggest that CE and ACAT-1 might be a novel therapeutic target for GR in BTC.

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Funding

No sources of funding were used to assist in the preparation of this study.

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Authors and Affiliations

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

    Goro Ueno MD, Yoshifumi Iwagami MD, PhD, Shogo Kobayashi MD, PhD, Suguru Mitsufuji MD, Daisaku Yamada MD, PhD, Yoshito Tomimaru MD, PhD, Hirofumi Akita MD, PhD, Tadafumi Asaoka MD, PhD, Takehiro Noda MD, PhD, Kunihito Gotoh MD, PhD, Masaki Mori MD, PhD, Yuichiro Doki MD, PhD & Hidetoshi Eguchi MD, PhD

  2. Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan

    Masaki Mori MD, PhD

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  1. Goro Ueno MD
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  2. Yoshifumi Iwagami MD, PhD
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Correspondence to Shogo Kobayashi MD, PhD.

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Disclosure

Goro Ueno, Yoshifumi Iwagami, Shogo Kobayashi, Suguru Mitsufuji, Daisaku Yamada, Yoshito Tomimaru, Hirofumi Akita, Tadafumi Asaoka, Takehiro Noda, Kunihito Gotoh, Masaki Mori, Yuichiro Doki, and Hidetoshi Eguchi have no conflicts of interest to report.

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Ueno, G., Iwagami, Y., Kobayashi, S. et al. ACAT-1-Regulated Cholesteryl Ester Accumulation Modulates Gemcitabine Resistance in Biliary Tract Cancer. Ann Surg Oncol 29, 2899–2909 (2022). https://doi.org/10.1245/s10434-021-11152-1

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