Association of extensive RNA disruption with natural killer cell-mediated death of K562 chronic myelogenous leukemia cells

Abstract

Extensive degradation of tumour 28S and 18S ribosomal RNAs, coupled with the accumulation of ribosomal RNA degradation products, is associated with pathologic complete response and improved disease-free-survival in breast cancer patients. Various chemotherapy agents and cellular stressors are known to trigger this process, termed ‘RNA disruption’, in tumour cells. However, it’s unclear whether immunotherapies, with or without chemotherapy administration, also trigger RNA disruption. To address this question, we assessed the ability of natural killer (NK) cells to induce RNA disruption and cell death in K562 chronic myeloid leukemia cells in vitro. We found that NK cells strongly stimulated RNA disruption, cytotoxicity (loss of plasma membrane integrity) and cell death (generation of cells with a subG1 DNA content) in K562 cells. Pre-activation of NK cells with interleukin-2 or pre-treatment of K562 cells with the chemotherapy drug doxorubicin augmented RNA disruption in K562 cells. RNA degradation patterns looked very similar between NK cell-treated and doxorubicin-treated K562 cells. Our observations suggest that RNA disruption is strongly associated with cell death irrespective of the death-inducing stimulus and raise the prospect that tumour RNA disruption may be a useful biomarker for quantifying cancer patients’ response to immunotherapies, with or without co-administration of chemotherapy drugs.