Abstract
Cell adhesion to stromal support and the associated intracellular signaling are central to drug resistance, therefore blocking both has been effective in increasing drug sensitization in leukemia. The stromal Ser/Thr protein kinase C (PKC) has been found to be important for conferring protection to leukemic cells. We aimed at elucidating the intracellular signals connected to cell adhesion and to stromal PKC. We found that NF-κB and Akt were up-regulated in mesenchymal stem cells (MSC) after binding of B-cell acute lymphoblastic leukemia (B-ALL) cells. Nevertheless, Akt inhibition did not induce B-ALL cell detachment. In spite of a clear activation of the NF-κB signaling pathway after B-ALL cell binding (up-regulation NF-κB1/2, and down-regulation of the IKBε and IKBα inhibitors) and an important reduction in cell adhesion after NF-κB inhibition, sensitization to the drug treatment was not observed. This was opposite to the PKC inhibitors Enzastaurin and HKPS, a novel chimeric peptide inhibitor, that were able to increase sensitization to dexamethasone, methotrexate, and vincristine. PLCγ1, Erk1/2, and CREB appear to be related to PKC signaling and PKC effect on drug sensitization since they were contra-regulated by HKPS when compared to dexamethasone-treated cells. Additionally, PKC inhibition by HKPS, but not by Enzastaurin, in MSC reduced the activity of three ABC transporters in leukemic cells treated with dexamethasone, a new indirect mechanism to increase sensitization to drug treatment in B-ALL cells. Our results show the validity of targeting the functional characteristic acquired and modulated during cell-to-cell interactions occurring in the leukemic niche.
Highlights
Taking into consideration that many possible mechanisms exist that can be involved in drug resistance [37,39], and knowing that interactions between mesenchymal stem cells (MSC) and leukemia cells are diverse and complex, including cell-to-cell contacts, nanotunneling, exosomes, vesicles, and soluble factors [40,41,42], the aim of the present work was to gain a better understanding of the signaling molecules and mechanisms that could be involved in drug resistance induced indirectly by MSC in childhood B-cell acute lymphoblastic leukemia (B-Acute lymphoblastic leukemia (ALL))
We have recently shown that the pretreatment of MSC with typical and novel chimeric peptide protein kinase C (PKC) inhibitors, prior to the establishment of co-cultures, renders B-ALL cell lines and primary B-ALL cells more susceptible to treatment with dexamethasone (DEXA) [16]
We first studied whether the increased susceptibility to DEXA could be observed with other frontline drugs used for B-ALL after MSC PKC inhibition (Figure 1)
Summary
Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with diverse genetic alterations [1]. The survival rate has improved in the last decades, reaching 80–90%. Cure rates, after patients relapse, are much lower [2]. It is accepted that genetic diversity exists at both diagnosis and relapse and that these former leukemic clones derive from either major or minor clones at disease presentation [3]
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