Disruption of Man-6-P-Dependent Sorting to Lysosomes Confers IGF1R-Mediated Apoptosis Resistance

TL;DR

Disrupting Man-6-P sorting in lysosomes makes cells resistant to apoptosis, possibly through IGF1R pathway activation.

Contribution

Identifies IGF1R pathway hyperactivation as a novel mechanism of apoptosis resistance in Man-6-P sorting-deficient cells.

Findings

GNPTAB knockout HeLa cells are resistant to doxorubicin, chloroquine, staurosporine, and paclitaxel.

Apoptosis resistance in these cells is linked to hyperactivation of the IGF1R pathway.

Impaired Man-6-P sorting leads to expanded lysosomal populations and altered drug response.

Abstract

Mutations in GNPTAB underlie mucolipidosis II and mucolipidosis III α/β, which are inherited lysosomal storage disorders caused by a defective UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine phosphotransferase. As a result, newly synthesized acid hydrolases fail to acquire Mannose-6-Phosphate (Man-6-P) sorting signals, or do so to a lesser extent, and exhibit an impaired trafficking to lysosomes. Interestingly, we found that GNPTAB knockout HeLa cells are resistant to several cytotoxic agents: doxorubicin, chloroquine, staurosporine and paclitaxel. While we detected an increased trapping of weak bases in the expanded lysosomal population of these cells, which could reduce the effect of doxorubicin and chloroquine; the decreased cell response to staurosporine and paclitaxel suggested the involvement of alternative resistance mechanisms. Indeed, further investigation revealed that the hyperactivation of the Insulin-like Growth Factor 1 Receptor (IGF1R) pathway is a central player in the apoptosis resistance exhibited by Man-6-P sorting deficient cells.

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