ABBV-744 induces autophagy in gastric cancer cells by regulating PI3K/AKT/mTOR/p70S6k and MAPK signaling pathways

Kun Wang; Jiatong Tang; Shengxian Fan; Haochen Su; Ranran Yu; Yixuan Zhang; Hao Wu; Ying Lv; Shu Zhang; Xiaoping Zou

Neoplasia: An International Journal for Oncology Research (Nov 2023)

ABBV-744 induces autophagy in gastric cancer cells by regulating PI3K/AKT/mTOR/p70S6k and MAPK signaling pathways

Kun Wang,
Jiatong Tang,
Shengxian Fan,
Haochen Su,
Ranran Yu,
Yixuan Zhang,
Hao Wu,
Ying Lv,
Shu Zhang,
Xiaoping Zou

Affiliations

Kun Wang: Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, No. 321 Zhongshan Road, Nanjing 210008 Jiangsu, China; Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Nanjing University Institute of Pancreatology, Nanjing, China
Jiatong Tang: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
Shengxian Fan: Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School.Nanjing University, Nanjing, China
Haochen Su: Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing Medical University, Nanjing, China
Ranran Yu: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
Yixuan Zhang: Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
Hao Wu: Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
Ying Lv: Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, No. 321 Zhongshan Road, Nanjing 210008 Jiangsu, China; Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Nanjing University Institute of Pancreatology, Nanjing, China; Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China; Corresponding authors at: Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, No. 321 Zhongshan Road, Nanjing 210008 Jiangsu, China.
Shu Zhang: Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, No. 321 Zhongshan Road, Nanjing 210008 Jiangsu, China; Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Nanjing University Institute of Pancreatology, Nanjing, China; Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China; Corresponding authors at: Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, No. 321 Zhongshan Road, Nanjing 210008 Jiangsu, China.
Xiaoping Zou: Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, No. 321 Zhongshan Road, Nanjing 210008 Jiangsu, China; Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Nanjing University Institute of Pancreatology, Nanjing, China; Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China; Department of Gastroenterology, Affilated Taikang Xianlin Drum Tower Hospital, Medical school of Nanjing University, Nanjing, Jiangsu, China; Corresponding authors at: Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, No. 321 Zhongshan Road, Nanjing 210008 Jiangsu, China.

Journal volume & issue: Vol. 45
p. 100936

Abstract

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The mortality rates of gastric cancer remain high due to limited therapeutic strategies. As a highly selective inhibitor of the BD2 domain of BET family proteins, ABBV-744 has potent chemotherapeutic activity against various human solid tumors. However, whether ABBV-744 has potential anti-tumor effects in gastric cancer remain largely unknown. In this study, we evaluated the effect of ABBV-744 on gastric cancer cells and explored the possible underlying mechanisms. We found that ABBV-744 inhibited the growth of gastric cancer cells and patient-derived tumor organoids in a dose-dependent manner. Cellular experiments revealed that ABBV-744 induced mitochondria damage, reactive oxygen species accumulation, cell cycle arrest and apoptotic cell death in gastric cancer cells. Transcriptomic analysis using RNA-sequencing data identified autophagy as a crucial pathway involved in the cell death caused by ABBV-744. Mechanically, further studies showed that ABBV-744 induced autophagy flux in gastric cancer cells by inactivating PI3K/AKT/mTOR/p70S6k and activating the MAPK signaling pathways. In vivo mouse xenograft studies demonstrated that ABBV-744 significantly suppressed the growth of gastric cancer cells via inducing autophagy. Taken together, our results suggest that ABBV-744 is a novel drug candidate for gastric cancer.

Published in Neoplasia: An International Journal for Oncology Research

ISSN: 1522-8002 (Print); 1476-5586 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: http://www.journals.elsevier.com/neoplasia/

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