LMW-PTP targeting potentiates the effects of drugs used in chronic lymphocytic leukemia therapy

Abstract

BackgroundLow molecular weight protein tyrosine phosphatase (LMW-PTP) is overexpressed in different cancer types and its expression is related to more aggressive disease, reduced survival rate and drug resistance. Morin is a natural polyphenol which negatively modulates, among others, the activity of LMW-PTP, leading to the potentiation of the effects of different antitumoral drugs, representing a potential beneficial treatment against cancer.MethodsLMW-PTP levels were measured by immunoblot analysis both in CLL cells from patients and in chronic lymphocytic leukemia (CLL)-derived Mec-1 cells. Cell viability was assessed in Mec-1 cells treated with morin alone or in combination with either fludarabine or ibrutinib or following siRNA-mediated LMW-PTP knockdown. Furthermore, the expression levels of VLA-4 and CXCR4 were assessed by both qRT-PCR and flow cytometry and both adhesion to fibronectin-coated plates and migration toward CXCL12 were analyzed in Mec-1 cells treated with morin alone or in combination with fludarabine or ibrutinib.ResultsWe observed that LMW-PTP is highly expressed in Mec-1 cells as well as in leukemic B lymphocytes purified from CLL patients compared to normal B lymphocytes. Morin treatment strongly decreased LMW-PTP expression levels in Mec-1 cells and potentiated the anticancer properties of both fludarabine and ibrutinib by increasing their apoptotic effects on leukemic cells. Moreover, morin negatively regulates adhesion and CXCL12-dependent migration of Mec-1 cells by affecting VLA-4 integrin expression and CXCR4 receptor recycling.ConclusionsMorin treatment in CLL-derived Mec-1 cell line synergizes with conventional anticancer drugs currently used in CLL therapy by affecting leukemic cell viability and trafficking.Electronic supplementary materialThe online version of this article (10.1186/s12935-019-0786-1) contains supplementary material, which is available to authorized users.

Morin-5′-Sulfonic Acid Sodium Salt (NaMSA) Attenuates Cyclophosphamide-Induced Histological Changes in Genitourinary Tract in Rats—Short Report

“…In vitro morin protects from apoptosis of renal proximal tubular cells (HK-2 cell line) caused by endoplasmic reticulum stress [31]. Recent studies also suggest that morin may increase anticancer activity of some conventional anticancer agents, e.g., fludarabine, inhibiting low molecular weight protein tyrosine phosphatase (LMW-PTP) [32], and may inhibit proliferation, migration, and invasion of EJ cells of bladder cancer via many different intracellular mechanisms [33].…”

p66Shc deficiency in CLL cells enhances PD-L1 expression and suppresses immune synapse formation

“…CLL cells have a profound defect in the expression of the pro-apoptotic and pro-oxidant adaptor p66Shc ( Capitani et al, 2010 ), that progressively further decreases during disease development ( Capitani et al, 2019 ; Patrussi et al, 2021a ). Since CLL cells suppress the ability of T cells to form ISs ( Ramsay et al, 2012 ), we asked whether the p66Shc defect impinges on the IS-suppressive abilities of CLL cells.…”

Low molecular weight protein tyrosine phosphatase as signaling hub of cancer hallmarks

“…Importantly, the knockdown of LMWPTP in Lucena-1 cells culminated in the inactivation of Bcr-Abl, which is well known to have a relevant contribution in leukemogenesis [4]. The inhibition of LMWPTP by Morin was also associated to chemotherapeutical sensitizer (see more details below) [41,42].…”

“…As an anti-tumor agent, at µM concentration, morin has been described to play a different role in cancer cell metabolism: (i) the anti-tumor activity is associated to DNA damage protection and ROS controlling [73]; (ii) apoptosis induction by caspase-3 and Bax activation [74]; (iii) inhibition of NFκB and Akt pathway [75][76][77]. Despite the broad mechanism of action, morin was able to increase the in vitro chemotherapeutical sensitivity, including in chemoresistance melanoma, prostate cancer, leukemia cell lines by decreasing LMWPTP expression [41,42], the effect observed also in vivo [78]. Morin acted as a non-competitive inhibitor of LMWPTP, at µM range, and triggered transient degradation of LMWPTP through the proteasome-dependent mechanism on the cancer cells [42].…”