Abstract
Recent studies have demonstrated that P-glycoprotein (P-gp) expression impairs DNA interstrand cross-linking agent-induced DNA repair efficiency in multidrug-resistant (MDR) cells. To date, the detailed molecular mechanisms underlying how P-gp interferes with Src activation and subsequent DNA repair activity remain unclear. In this study, we determined that the C-terminal Src kinase-binding protein (Cbp) signaling pathway involved in the negative control of Src activation is enhanced in MDR cells. We also demonstrated that cells that ectopically express P-gp exhibit reduced activation of DNA damage response regulators, such as ATM, Chk2, Braca1 and Nbs1 and hence attenuated DNA double-strand break repair capacity and become more susceptible than vector control cells to DNA interstrand cross-linking (ICL) agents. Moreover, we demonstrated that P-gp can not only interact with Cbp and Src but also enhance the formation of inhibitory C-terminal Src kinase (Csk)-Cbp complexes that reduce phosphorylation of the Src activation residue Y416 and increase phosphorylation of the Src negative regulatory residue Y527. Notably, suppression of Cbp expression in MDR cells restores cisplatin-induced Src activation, improves DNA repair capacity, and increases resistance to ICL agents. Ectopic expression of Cbp attenuates cisplatin-induced Src activation and increases the susceptibility of cells to ICL agents. Together, the current results indicate that P-gp inhibits DNA repair activity by modulating Src activation via Cbp-Csk-Src cascade. These results suggest that DNA ICL agents are likely to have therapeutic potential against MDR cells with P-gp-overexpression.
Highlights
Multidrug resistance (MDR) is a significant obstacle to the success of chemotherapy in cancer patients [1]
P-gp acts as an efflux pump responsible for preventing the delivery of various chemotherapeutic agents to cancer cells, several reports have demonstrated that increased P-gp levels enhance the sensitivity of MDR cancer cells to various DNA-damaging agents, such as cisplatin, bis-chloroethylnitrosourea, and gemcitabine www.impactjournals.com/oncotarget
We revealed mechanistic insights regarding how P-gp interferes with Src activation and DNA repair activity
Summary
Multidrug resistance (MDR) is a significant obstacle to the success of chemotherapy in cancer patients [1]. MDR may be attributed to various mechanisms, it is often associated with increased expression of ATPbinding cassette (ABC) transporter family members, which extrude anticancer drugs out of cells [2, 3]. Overexpression of P-gp in tumor tissues is a prognostic indicator associated with poor response to chemotherapy and poor clinical outcome [7,8,9]. Numerous agents have been identified or developed to modify, modulate, or reverse the P-gpmediated MDR phenotype [1, 10, 11]. Most of those agents were terminated during clinical trials because of their toxicities or unexpected outcomes [12]. Developing novel agents against P-gp and targeting alternative mechanisms that sensitize MDR cells to therapeutic agents may represent new paths toward overcoming MDR [11, 13]
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