An active IGF-1R-AKT signaling imparts functional heterogeneity in ovarian CSC population.

Ram K Singh,Asmita Sakpal,Abhijit De,Pritha Ray,Ajit Dhadve

doi:10.1038/srep36612

Abstract

Deregulated IGF-1R-AKT signaling influences multiple nodes of cancer cell physiology and assists in migration, metastasis and acquirement of radio/chemoresistance. Enrichment of cancer stem cells (CSC) positively correlates with radio/chemoresistance development in various malignancies. It is unclear though, how IGF-1R-AKT signalling shapes CSC functionality especially in ovarian cancer. Previously we showed that upregulated IGF-1R expression is essential to initiate platinum-taxol resistance at early stage which declines with elevated levels of activated AKT at late resistant stage in ovarian cancer cells. Here, we investigated the effect of this oscillatory IGF-1R-AKT signalling upon CSC functionality during generation of chemoresistance. While gradual increase in CSC properties from early (ER) to late (LR) resistant stages was observed in three different (cisplatin/paclitaxel/cisplatin-paclitaxel) cellular models created in two ovarian cancer cell lines, the stemness gene expressions (oct4/sox2/nanog) reached a plateau at early resistant stages. Inhibition of IGF-1R only at ER and AKT inhibition only at LR stages significantly abrogated the CSC phenotype. Interestingly, real time bioluminescence imaging showed CSCs of ER stages possessed faster tumorigenic potential than CSCs belonging to LR stages. Together, our data suggest that IGF-1R-AKT signalling imparts functional heterogeneity in CSCs during acquirement of chemoresistance in ovarian carcinoma.

Highlights

Insulin like Growth Factor-1 Receptor (IGF-1R) is a transmembrane receptor tyrosine kinase which transmits signal via PI3K-AKT or MAPK-ERK pathways[1,2,3]
We have previously developed dynamic models of drug resistance against cisplatin, paclitaxel and both drugs by treating A2780 and OAW42 ovarian cancer cell lines with successive and gradually incrementing drug concentration and categorized them into early (ER) (CisER, PacER and DualER)and late (LR) (CisLR, PacLR and DualLR) resistant stages depending on their resistant indices[20]
The quiescent and resistant nature of the cancer stem cells act as double edged sword to battle the therapeutic effects of cytotoxic drugs especially for those which target replication machinery of the cells

Summary

Introduction

Insulin like Growth Factor-1 Receptor (IGF-1R) is a transmembrane receptor tyrosine kinase which transmits signal via PI3K-AKT or MAPK-ERK pathways[1,2,3]. Overlapping presence of these biomarkers in normal cell types poses a real challenge for targeting CSCs. In congruence with intratumoral heterogeneity, recent evidences suggest that CSCs are not uniform but rather heterogeneous population and highly plastic in nature[13,14,15]. Using indigenously developed resistant models against cisplatin, paclitaxel and dual drugs in ovarian cancer cells, we showed that upregulated IGF-1R expression is crucial to initiate resistance and an activated AKT later www.nature.com/scientificreports/. Inhibition of AKT relieved IGF-1R suppression and sensitized the late resistant cells to combinatorial treatments This is the first report on an intricate and interdependent relation between IGF-1R and AKT with functional heterogeneity of ovarian cancer stem cells which might emerge as a therapeutic target for the resistant disease

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Results

Conclusion