Berberine Induces Autophagic Cell Death in Acute Lymphoblastic Leukemia by Inactivating AKT/mTORC1 Signaling

Abstract

Introduction

Berberine has been reported to inhibit cancer cell growth by apoptosis induction and exhibits a protective role against cancer progression. The current study aims to investigate the effects of berberine on acute lymphoblastic leukemia (ALL) and the mechanism beyond apoptosis.

Methods

Cell viability was determined in ALL cell lines EU-6 and SKW-3 using trypan blue staining. Cell autophagy was determined by immunofluorescence and Western blot. ALL xenograft mice were established to investigate the anti-tumor effects of BBR. The molecular mechanism was explored in ALL cell lines using siRNA and signaling inhibitors.

Results

Herein, we show that berberine treatment significantly inhibits ALL cell viability and promotes cell death by inducing autophagy in a dose-dependent manner. Moreover, berberine significantly alleviates the aggressive pathological condition in ALL xenograft mice. Mechanistic studies exhibit that berberine induces autophagic death in ALL cells by inactivating AKT/mTORC1 signaling. Chemically targeting AKT/mTORC1 signaling controls berberine-induced cell autophagy in vitro, and blockade of autophagic process blunts berberine-alleviated pathological condition in vivo.

Discussion

In conclusion, our study reveals that berberine could induce ALL cell autophagic death by inactivating AKT/mTORC1 signaling that could be used to develop small molecule drug for ALL treatment.

Keywords:

• acute lymphoblastic leukemia
• berberine
• AKT/mTORC1
• autophagy

Abbreviations

BBR, berberine; ALL, acute lymphoblastic leukemia; PDIA6, protein disulfide isomerase family 6; WT, wild type; WBC, white blood cell; RBC, red blood cell; ATGs, autophagy-related genes; ATCC, American Type Culture Collection; HRP, horseradish peroxidase; i.v, intravenously; LC3, light chain 3; ER, endoplasmic reticulum.

Disclosure

The authors declare no conflicts of interest in this work.