1. Academic Validation
  2. AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth

AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth

  • Cell Death Dis. 2021 Apr 6;12(4):365. doi: 10.1038/s41419-021-03655-2.
Ying-Chen Xia  # 1 Jian-Hua Zha  # 1 Yong-Hua Sang  # 2 Hui Yin 1 Guo-Qiu Xu 1 Jie Zhen 3 Yan Zhang 4 Ben-Tong Yu 5
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China.
  • 2 Department of Thoracic Surgery, The Second affiliated Hospital of Soochow University, Suzhou, China.
  • 3 Department of Thoracic Surgery, Qidong People's Hospital, Qidong, China.
  • 4 Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China. [email protected].
  • 5 Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China. [email protected].
  • # Contributed equally.
Abstract

Activation of adenosine monophosphate-activated protein kinase (AMPK) is able to produce significant anti-non-small cell lung Cancer (NSCLC) cell activity. ASP4132 is an orally active and highly effective AMPK Activator. The current study tested its activity against NSCLC cells. In primary NSCLC cells and established cell lines (A549 and NCI-H1944) ASP4132 potently inhibited cell growth, proliferation and cell cycle progression as well as cell migration and invasion. Robust Apoptosis activation was detected in ASP4132-treated NSCLC cells. Furthermore, ASP4132 treatment in NSCLC cells induced programmed necrosis, causing mitochondrial p53-cyclophilin D (CyPD)-adenine nucleotide translocase 1 (ANT1) association, mitochondrial depolarization and medium Lactate Dehydrogenase release. In NSCLC cells ASP4132 activated AMPK signaling, induced AMPKα1-ACC phosphorylation and increased AMPK activity. Furthermore, AMPK downstream events, including mTORC1 inhibition, Receptor Tyrosine Kinases (PDGFRα and EGFR) degradation, Akt inhibition and Autophagy induction, were detected in ASP4132-treated NSCLC cells. Importantly, AMPK inactivation by AMPKα1 shRNA, knockout (using CRISPR/Cas9 strategy) or dominant negative mutation (T172A) almost reversed ASP4132-induced anti-NSCLC cell activity. Conversely, a constitutively active AMPKα1 (T172D) mimicked and abolished ASP4132-induced actions in NSCLC cells. In vivo, oral administration of a single dose of ASP4132 largely inhibited NSCLC xenograft growth in SCID mice. AMPK activation, mTORC1 inhibition and EGFR-PDGFRα degradation as well as Akt inhibition and Autophagy induction were detected in ASP4132-treated NSCLC xenograft tumor tissues. Together, activation of AMPK by ASP4132 potently inhibits NSCLC cell growth in vitro and in vivo.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-136447
    99.32%, AMPK Activator