Cell adhesion to collagen promotes leukemia resistance to doxorubicin by reducing DNA damage through the inhibition of Rac1 activation

Abstract

Chemoresistance is a major hurdle in anti-cancer therapy. Growing evidence indicates that integrin-mediated cell adhesion to extracellular matrix plays a major role in chemoresistance. However, the underlying mechanisms are not fully understood. We have previously shown that the collagen-binding integrin α2β1 promoted doxorubicin resistance in acute T cell lymphoblastic leukemia (T-ALL). In this study, we found that acute myeloid leukemia (AML) cell lines also express α2β1 integrin and collagen promoted their chemoresistance as well. Furthermore, we found that high levels of α2 integrin correlate with worse overall survival in AML. Our results showed that doxorubicin-induced apoptosis in leukemic cells is associated with activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) and that collagen inhibited this pathway. The protective effect of collagen is associated with the inhibition of Rac1-induced DNA damage as evaluated by the comet assay and the phosphorylated levels of histone H2AX (γ-H2AX). Together these results show that by inhibiting pro-apoptotic Rac1, α2β1 integrin can be a major pathway protecting leukemic cells from genotoxic agents and may thus represent an important therapeutic target in anti-cancer treatment.

Reciprocal Interplay Between Fibrillar Collagens and Collagen-Binding Integrins: Implications in Cancer Progression and Metastasis

“…Implication of α2β1 integrin in tumor progression and metastasis was reported in several other types of cancers, including pancreatic, colorectal, gastric and lung cancers, oral squamous cell carcinoma and T-cell acute lymphoblastic leukemia, which were previously reviewed in ( 319 ). Lastly, it has been reported that α2β1 integrin and collagen I participate to doxorubicin-induced drug resistance in leukemia by either protecting leukemia cells from apoptosis through MAPK/ERK pathway activation ( 317 ), or by decreasing the DNA damage through the inhibition of Rac1 activation ( 318 ).…”

The Extracellular Bone Marrow Microenvironment—A Proteomic Comparison of Constitutive Protein Release by In Vitro Cultured Osteoblasts and Mesenchymal Stem Cells

“…Such quantitative differences in the release of extracellular regulators may contribute to the previously described differences among various stem cell niches in their regulation of normal hematopoiesis [ 3 ]. Many of the extracellular regulators involved in normal hematopoiesis are also important in leukemic hematopoiesis although their function in leukemic hematopoiesis is less well characterized; e.g., collagen/integrin/Rac1 [ 56 , 57 ], the CDH1 [ 58 ] and CDH2 cadherins [ 59 ], thrombospondin [ 60 , 61 ], TGFβ [ 62 , 63 , 64 ], osteopontin [ 65 ] and LOX/lipid metabolism [ 66 , 67 ] all seem to be important for leukemogenesis and/or chemosensitivity in hematological malignancies.…”

Cadherins, Selectins, and Integrins in CAM-DR in Leukemia

“…a 2 b 1 mediated adhesion activates the MAPK/ERK pathway, which inhibits the doxorubicin-induced activation of c-Jun N-terminal kinase (JNK) and maintains the pro-survival protein Bcl-2 family member Mcl-1. The same group extended a 2 b 1-collagen mediated doxorubicin resistance in the AML cell lines HL-60 and U937 (165). In AML, collagen binding through a 2 b 1 inhibited the activation of the pro-apoptotic protein Rac1, thereby preventing Rac1 induced DNA damage.…”

“…Integrin a2b1 binds to collagen and upregulates ABCC1 via the ERK/MAPK pathways to modulate efflux (221). Similarly, collagen-binding b1 integrins contribute to doxorubicin resistance in AML by reducing DNA damage through Rac1 inhibition (222).…”