Heat Shock Protein 27 as a Biomarker Predicting the Role of Chemotherapy-Induced Autophagy on Drug Sensitivity

Lung metastasis constitutes the main cause of death in osteosarcoma (OS) patients. We reported that aerosol Gemcitabine (GCB) has a significant therapeutic effect against OS lung metastases[1]. However, a subset of cells failed to respond to GCB resulting in persistent small isolated lung metastases. Autophagy [2], a catabolic process involved in cellular homeostasis, can either be protective or promote cell death. Our in vitro and in vivo studies demonstrated that autophagy plays a role in OS response to GCB. GCB induces autophagy in several different OS cell lines including the human LM7 and CCH-OS-D. Blocking autophagy using Hydroxychloroquine and/or the downregulation of Beclin 1 increased the sensitivity of LM7 cells to GCB but decreased the sensitivity of CCH-OS-D cells. This dual role of autophagy has been described in other tumor types. However, predicting whether blocking autophagy will increase or decrease drug-sensitivity has not been described. We found that the induction of phosphorylated heat shock protein 27 (pHsp27) following drug exposure with camptothecin or GCB correlated with the role of autophagy in drug sensitivity. Blocking autophagy in cells whose pHsp27 was increased following chemotherapy resulted in enhanced drug sensitivity whereas blocking autophagy in cells where pHsp27 was decreased resulted in reduced drug sensitivity. In conclusion, induction of pHsp27 following chemotherapy predicts whether blocking autophagy will increase or decrease drug sensitivity.

1. Gordon, N. and E.S. Kleinerman, Aerosol therapy for the treatment of osteosarcoma lung metastases: targeting the Fas/FasL pathway and rationale for the use of gemcitabine. Journal of aerosol medicine and pulmonary drug delivery, 2010. 23(4): p. 189-96.
2. Chen, N. and J. Debnath, Autophagy and tumorigenesis. FEBS Lett, 2010. 584(7): p. 1427-35.