Study summary · research use only
LCP2 mediates SUV39H1-driven cellular senescence-related chemoresistance in natural killer/T-cell lymphoma
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study examined mechanisms of chemoresistance in natural killer/T-cell lymphoma (NKTCL) using multidrug-resistant models established with adriamycin (ADM), proteomic and phosphoproteomic analysis of plasma from clinical patients and resistant cells, and an in vivo ageing microenvironment model (species not specified). LCP2 was identified as a protein reduced in the plasma of relapsed/refractory NKTCL patients and in chemoresistant cells, correlating inversely with the senescence marker SA-β-gal. LCP2 knockdown was associated with increased chemoresistance, senescence-associated secretory phenotype secretion, and G0/G1 cell cycle arrest. LCP2 deficiency was linked to activation of the IQGAP2/LaminA/C/SUV39H1 axis, associated with DNA damage, telomere stress-induced senescence, and an immunosuppressive microenvironment. Targeting this axis with Epitalon and Chaetocin was reported to partially eliminate therapy-induced senescent cells, enhance response to chemotherapeutics, and reduce the immunosuppressive microenvironment in vivo.
Abstract
Natural killer/T-cell lymphoma (NKTCL) is an aggressive haematological malignancy with poor prognosis, particularly in patients with relapsed/refractory (R/R) disease. The mechanisms underlying multidrug resistance in NKTCL remain unclear and present an urgent challenge that must be addressed during clinical treatment. Multidrug-resistant NKTCL models were established using adriamycin (ADM), and cellular senescence was confirmed by markers including P16, P21, and senescence-associated β-galactosidase (SA-β-gal). Proteomic sequencing of plasma from clinical patients and resistant cells identified LCP2 as a key protein. Phosphoproteomics, mass spectrometry, and co-immunoprecipitation analyses revealed LCP2's role in mediating senescence-associated chemoresistance. An in vivo ageing microenvironment model was used to assess whether targeting the LCP2-mediated axis could eliminate chemoresistant senescent cells. Results show that ADM-resistant NKTCL cells exhibited phenotypic and senescence features. Of these, LCP2 expression was significantly reduced in the plasma of R/R NKTCL patients and in chemoresistant cells, correlating inversely with senescence marker SA-β-gal. Moreover, LCP2 knockdown enhanced the chemoresistance, senescent-associated secretory phenotype secretion, and G0/G1 cell cycle arrest in NKTCL cells. Mechanistically, LCP2 deficiency activated the IQGAP2/LaminA/C/SUV39H1 axis, thus driving DNA damage, telomere stress-induced senescence, and facilitating the formation of an immunosuppressive microenvironment. Importantly, targeting this axis with Epitalon and Chaetocin can partially eliminate therapy-induced senescent cells, enhance response to chemotherapeutics, and alleviate the immunosuppressive microenvironment to a certain extent in vivo. In conclusion, this study is the first to uncover LCP2 as a critical biomarker of senescence-related chemoresistance in NKTCL, providing a theoretical basis for the clinical translation of senolytics for treating R/R NKTCL.
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