2-Oxonanonoidal Antibiotic Actinolactomycin Inhibits Cancer Progression by Suppressing HIF-1α.

Jiadong Cheng,Linchong Sun,Caixia Suo,Lan Hu,Chengbin Cui,Zheng Yang,Yueyang Jack Wang,Ping Gao

doi:10.3390/cells8050439

Abstract

HIF-1 serves as an important regulator in cell response to hypoxia. Due to its key role in promoting tumor survival and progression under hypoxia, HIF-1 has become a promising target of cancer therapy. Thus far, several HIF-1 inhibitors have been identified, most of which are from synthesized chemical compounds. Here, we report that ALM (ActinoLactoMycin), a compound extracted from metabolites of Streptomyces flavoretus, exhibits inhibitory effect on HIF-1α. Mechanistically, we found that ALM inhibited the translation of HIF-1α protein by suppressing mTOR signaling activity. Treatment with ALM induced cell apoptosis and growth inhibition of cancer cells both in vitro and in vivo in a HIF-1 dependent manner. More interestingly, low dose of ALM treatment enhanced the anti-tumor effect of Everolimus, an inhibitor of mTOR, suggesting its potential use in combination therapy of tumors, especially solid tumor patients. Thus, we identified a novel HIF-1α inhibitor from the metabolites of Streptomyces flavoretus, which shows promising anti-cancer potential.

Highlights

Hypoxia is one of the most important characteristics of solid tumor microenvironment as a result of cancer cells’ malignant proliferation and lacking of blood supply caused by abnormal structure of vessels in tumor [1,2]
Our results further demonstrated that ALM blocked HIF-1α protein synthesis via inhibiting Akt and Mammalian target of rapamycin (mTOR) signaling
There has been an intense interest in developing novel therapeutic strategies to target HIF-1α in cancer therapy for the following reasons: (1) HIF-1α expression has been found high in the majority of tumors, especially solid tumor, because of hypoxia, (2) hypoxia-inducible factor 1 (HIF-1) is a master regulator for many aspects in cancer biology, and (3) inhibition of HIF-1α may exploit tumor hypoxia by converting it from a treatment obstacle into a targeting advantage

Summary

Introduction

Hypoxia is one of the most important characteristics of solid tumor microenvironment as a result of cancer cells’ malignant proliferation and lacking of blood supply caused by abnormal structure of vessels in tumor [1,2]. Tumor cells suffer from the lack of O2 , nutritional deficiencies and low pH under hypoxia, while hypoxia-inducible factor 1 (HIF-1) serves as the major player in cell survival in that case [3,4]. HIF-1 regulates hundreds of genes involved in invasion/metastasis, vascularization, genetic instability and treatment failure, making it critical in cancer pathogenesis [5,6,7,8]. Clinical results showed that HIF-1 is overexpressed in most solid tumors and positively correlated with poor prognosis in cancer patients. Targeting HIF-1 became a promising strategy to treat cancer [15,16,17,18,19]

Methods

Results

Conclusion