Inactivation of the Akt/FOXM1 Signaling Pathway by Panobinostat Suppresses the Proliferation and Metastasis of Gastric Cancer Cells.

Na-Ri Lee,Seong-Hun Kim,Ok Hee Chai,Da-Yeah Kim,Soo Mi Kim,Ruoyu Meng,Byung-Hyun Park,Hua Jin

doi:10.3390/ijms22115955

Abstract

Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Histone deacetylase (HDAC) inhibitors are a new class of cytostatic agents available for the treatment of various cancers and diseases. Although numerous clinical and pre-clinical trials on the anticancer effects of panobinostat have been conducted, only a few reports have investigated its efficacy in gastric cancer. The present study aimed to investigate the effects of panobinostat in gastric cancer cells. Panobinostat significantly inhibited the cell viability and proliferation of the gastric cancer cell lines SNU484 and SNU638 in a dose-dependent manner; it reduced the colony-forming ability of these cells. Moreover, it induced apoptosis as indicated by increased protein levels of cleaved poly ADP-ribose polymerase and cleaved caspase-3. Panobinostat induced the G2/M cell cycle arrest in SNU484 and SNU638 cells and subsequently decreased the G2/M phase regulatory-associated protein expression of p-Wee1, Myt1, and Cdc2. Furthermore, panobinostat significantly inhibited the metastasis of SNU484 and SNU638 cells by regulating the expression of MMP-9 and E-cadherin. Further, it decreased the protein levels of p-Akt and forkhead box protein M1 (FOXM1). These effects were reversed by the Akt agonist SC79 and were accelerated by the Akt inhibitor LY2940002. Moreover, tumor growth in xenograft animal experiments was suppressed by panobinostat. These results indicated that panobinostat inhibits the proliferation, metastasis, and cell cycle progression of gastric cancer cells by promoting apoptosis and inactivating Akt/FOXM1 signaling. Cumulatively, our present study suggests that panobinostat is a potential drug for the treatment of gastric cancer.

Highlights

Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide [1]
Our results indicated that panobinostat suppresses cell proliferation, cell cycle progression, cell migration, and cell metastasis via inactivating Akt/forkhead box protein M1 (FOXM1) signaling in GC, suggesting that panobinostat offers a novel treatment strategy for GC
Panobinostat induced histone acetylation in a dosedependent manner, no change was observed with histone H3 and H4 in SNU484 and SNU638 GC cells (Figure 1A)

Summary

Introduction

Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide [1]. GC is a major health concern, with over 1 million new cases globally each year [2]. Owing to metastatic recurrence, the prognosis 4.0/). For patients with advanced GC remains poor [3,4]. The development of novel chemotherapies is urgently required to control GC progression and recurrence. Histone deacetylase (HDAC) inhibitors exhibit their tumor-suppressive effects by increasing the acetylation of histones and non-histone proteins, thereby regulating gene transcription and leading to the induction of apoptosis, differentiation, and degradation of misfolded proteins [5]. Various classes of HDAC inhibitors have been investigated for their potential antitumor effects. Vorinostat is approved for the treatment of advanced primary cutaneous

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Discussion

Conclusion