Abstract
Autophagy is a double-edged sword in tumorigenesis and plays an important role in the resistance of cancer cells to chemotherapy. S100A8 is a member of the S100 calcium-binding protein family and plays an important role in the drug resistance of leukemia cells, with the mechanisms largely unknown. Here we report that S100A8 contributes to drug resistance in leukemia by promoting autophagy. S100A8 level was elevated in drug resistance leukemia cell lines relative to the nondrug resistant cell lines. Adriamycin and vincristine increased S100A8 in human leukemia cells, accompanied with upregulation of autophagy. RNA interference-mediated knockdown of S100A8 restored the chemosensitivity of leukemia cells, while overexpression of S100A8 enhanced drug resistance and increased autophagy. S100A8 physically interacted with the autophagy regulator BECN1 and was required for the formation of the BECN1-PI3KC3 complex. In addition, interaction between S100A8 and BECN1 relied upon the autophagic complex ULK1-mAtg13. Furthermore, we discovered that exogenous S100A8 induced autophagy, and RAGE was involved in exogenous S100A8-regulated autophagy. Our data demonstrated that S100A8 is involved in the development of chemoresistance in leukemia cells by regulating autophagy, and suggest that S100A8 may be a novel target for improving leukemia therapy.
Highlights
Autophagy is a catabolic process involving the degradation of intracellular aggregated or misfolded proteins, and damaged organelles through lysosomal machinery in response to stress or starvation [1,2]
We found that S100A8 protein was significantly increased in the drug resistance leukemia cell line K562/A02, relative to the nondrug resistant cell line K562 (Fig. 1A)
These results showed that drug-resistant leukemia cells overexpress S100A8
Summary
Autophagy is a catabolic process involving the degradation of intracellular aggregated or misfolded proteins, and damaged organelles through lysosomal machinery in response to stress or starvation [1,2]. Deregulation of autophagy is implicated in several human diseases including cancers. Depending on the type of tumor and stage of disease, autophagy induces both tumor cell survival and death during the initiation, progression, maturation and maintenance of cancer [3]. It has been well documented that autophagy plays an important role in the resistance of cancer cells to chemotherapy [4]. We recently found that damage associated molecular pattern molecules (DAMPs) such as high mobility group box 1 (HMGB1) contribute to chemotherapy resistance though upregulating autophagy in leukemia [7]. S100A8 is involved in the progression of various cancers, including leukemia, and induces cell death by functional linkage with Bcl-2 family members [10,11,12,13,14]. The data suggest that S100A8 contributes to chemoresistance via regulating the autophagy in leukemia
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