Marine lipopeptide Iturin A inhibits Akt mediated GSK3β and FoxO3a signaling and triggers apoptosis in breast cancer.

Goutam Dey,Mahitosh Mandal,Rashmi Bharti,Subhasis Das,B N Prashanth Kumar,Ramkrishna Sen,Kaushik Kumar Dey,Gunaseelan Dhanarajan

doi:10.1038/srep10316

Goutam Dey, Mahitosh Mandal + Show 6 more

Open Access

https://doi.org/10.1038/srep10316

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Journal: Scientific Reports	Publication Date: May 14, 2015
Citations: 99	License type: CC BY 4.0

Affiliation: Indian Institute of Technology Kharagpur

Abstract

Akt kinase is a critical component of the PI3K/Akt signaling pathway, which is frequently over expressed in human cancers including breast. Therapeutic regimens for inhibiting breast cancer with aberrant Akt activity are essential. Here, we evaluated antitumor effect of a marine bacteria derived lipopeptide ‘Iturin A’ on human breast cancer in vitro and in vivo through disrupting Akt pathway. Proliferation of MDA-MB-231 and MCF-7 breast cancer cells were significantly inhibited by Iturin A and it induced apoptosis as confirmed by increased Sub G1 populations, DNA fragmentation, morphological changes and western blot analysis. Furthermore, Iturin A inhibited EGF induced Akt phosphorylation (Ser473 and Thr308) and its downstream targets GSK3β and FoxO3a. Iturin A inactivated MAPK as well as Akt kinase leading to the translocation of FoxO3a to the nucleus. Gene silencing of Akt in MDA-MB-231 and MCF-7 cells reduced the sensitivity of cancer cells to Iturin A. Interestingly, overexpression of Akt with Akt plasmid in cancer cells caused highly susceptible to induce apoptosis by Iturin A treatment. In a xenograft model, Iturin A inhibited tumor growth with reduced expressions of Ki-67, CD-31, P-Akt, P-GSK3β, P-FoxO3a and P-MAPK. Collectively, these findings imply that Iturin A has potential anticancer effect on breast cancer.

Highlights

The menace of chemo-resistance of the cancer cells and a steady decline in the discovery of new lead anticancer molecules has thrown a formidable research challenge to the concerned scientific community
The elution time of standard Iturin A matched with that of first group of isoforms from the methanol extract, which indicated that this group consisted of Iturin A family of lipopeptides (Fig. 1A)
Translocation of FoxO3a to nucleus from cytoplasm was observed in Iturin A treated groups (Fig. 6E). These results suggested that Iturin A induced nuclear accumulation of FoxO3a to mediate apoptosis in MDA-MB-231 and MCF-7 cells

Summary

Introduction

The menace of chemo-resistance of the cancer cells and a steady decline in the discovery of new lead anticancer molecules has thrown a formidable research challenge to the concerned scientific community. It is developed due to a number of cellular and molecular transformations that lead to breast cancer cell proliferation and inhibition of apoptosis. These events involve disrupting various signaling networks and thereby resulting in altered gene expression. Activated FoxO3a triggers apoptosis or cell cycle arrest through down regulation of anti apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1) via Bim activation[9] Another substrate GSK3β (Ser9) induces cell apoptosis via multiple mechanisms[10]. Our research findings indicated that Iturin A induced antiproliferative and apoptotic effect in breast cancer cells in vitro and in vivo This apoptotic effect may be attributed to the inhibition of Akt kinase and its downstream targets FoxO3a and GSK3β

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