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

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.

New Hope for Pancreatic Ductal Adenocarcinoma Treatment Targeting Endoplasmic Reticulum Stress Response: A Systematic Review

“…In other tumour types like colorectal and breast cancer, the drug-specific activation of P38 selectively inhibited the self-renewal of cancer stem cells (CSC) through a reversal of stem cell markers (CD44 and CD133) and self-renewal factors (c-MYC and BMI-1). Thus, this study corroborated the recognised role of P38 as a tumour suppressor [ 97 ].…”

“…In other tumour types, ATF6α overexpression has been proposed to be a target against cancer stem cells (CSC), due to the nuclear translocation of ATF6α under the effect of tunicamycin in CSC population [ 77 ] ( Table 2 ). Recently, heparan hexasaccharide sulfate has been used with favourable results, selectively inhibiting CSC from PDAC and other solid tumours by activation of P38 [ 97 ] ( Table 1 and Table 2 ). Although there are studies with promising results concerning PDAC, there is still a lack of evidence to justify the use of ERSR activation as a target for proliferative pancreatic cancer and stem cells.…”

Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges

“…Heparin (unfractionated, low molecular weight and other derivatives) has been investigated in clinical trials for various forms of inflammation (116)(117)(118)(119), although it is not clear which sequences, if any, would offer the best response. A recent discovery that a HS hexasaccharide selectively targets cancer stem cells is exciting (120). Though HS is known to engage diverse mitogenic factors, this observation suggests that one or more HS oligosaccharides could display selectivity for a specific chemokine and thereby exhibit a distinct anti-inflammatory phenotype.…”

Perspective on computational simulations of glycosaminoglycans

“…Science is now advancing more in the direction of GAGs as informational molecules with some key sequences exhibiting promising biological activity. [1][2][3][4][5][6][7][8][9][10][11] The next frontier to be tackled is converting this information into drugs. This frontier presents major opportunities for computational chemist to make an impact, especially because GAGs are arguably the most diverse, natural linear biopolymers made from very few foundational saccharide units.…”

“…A back-of-the-envelope comparison of the number of unique, repeating 6-mers of GAGs with 6-mers of proteins and nucleic acids reveals astounding possibilities. Whereas there can be 4.096 × 10 3 distinct hexa-nucleotides (=4 6 ) from the four common nucleic acid bases, a hexa-peptide made up of the 20 common amino acids could any of the 6.4 × 10 6 sequences (=20 6 ). In contrast, a HP/HS repeating 6-mer can be any of the 12.2 × 10 9 sequences originating from a theoretical possibility of 48 unique, repeating disaccharide units.…”