Heparan sulfate hexasaccharide selectively inhibits cancer stem cells self-renewal by activating p38 MAP kinase.

Nirmita J Patel,Rio S Boothello,Somesh Baranwal,Umesh R Desai,Chetna Sharon,Bhaumik B Patel

doi:10.18632/oncotarget.12358

Nirmita J Patel, Rio S Boothello + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.12358

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Abstract

Heparan sulfate (HS) plays a role in the majority of essential hallmarks of cancer, yet its ability to modulate self-renewal, especially of cancer stem cells (CSCs), remains unknown. We have discovered that a non-anticoagulant HS hexasaccharide (HS06) sequence, but not other shorter or longer sequences, selectively inhibited CSC self-renewal and induced apoptosis in colorectal, pancreatic, and breast CSCs suggesting a very general phenomenon. HS06 inhibition of CSCs relied upon early and sustained activation of p38α/β mitogen activated protein kinase (MAPK) but not other MAPKs family members i.e. ERK and JNK. In contrast, polymeric HS induced exactly opposite changes in MAPK activation and failed to inhibit CSCs. In fact, TCF4 signaling, a critical regulator of CSC self-renewal, was inhibited by HS06 in a p38 activation dependent fashion. In conclusion, HS06 selectively inhibits CSCs self-renewal by causing isoform specific activation of p38MAPK to inhibit TCF4 signaling. These observations on chain length-induced specificity carry major mechanistic implications with regard to HS in cancer biology, while also presenting a novel paradigm for developing novel anti-CSC hexasaccharides that prevent cancer relapse.

Highlights

Complete cure of cancer is almost never achieved because all current anti-cancer agents primarily target the bulk of tumor, and not the small population of cancer stem cells (CSCs) that seed every tumor [1,2,3,4,5]
Using a robust chemical biology approach, we have discovered phenomenal specificity exhibited by Heparan sulfate (HS) of distinct chain length at the levels of a) the cancer cell and its b) signal transduction machinery
The specificity of the signaling is evident by differential activation of mitogen activated protein kinase (MAPK) family members in an isoform-specific manner

Summary

Introduction

Complete cure of cancer is almost never achieved because all current anti-cancer agents primarily target the bulk of tumor, and not the small population of cancer stem cells (CSCs) that seed every tumor [1,2,3,4,5]. CSCs may lay dormant before incidental activation, which may explain disease relapse [2, 7]. The CSC paradigm presents a major opportunity for developing novel agents that offer the possibility of permanent disease www.impactjournals.com/oncotarget cure. Several approaches have been presented with the goal of identifying anti-CSC agents [1, 8,9,10] and several clinical trials are currently in progress

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