Oncotarget

Research Papers:

Phosphorylated heat shock protein 27 as a potential biomarker to predict the role of chemotherapy-induced autophagy in osteosarcoma response to therapy

Janice M. Santiago-O’Farrill, Eugenie S. Kleinerman, Mario G. Hollomon, Andrew Livingston, Wei-Lien Wang, Jen-Wei Tsai and Nancy B. Gordon _

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Oncotarget. 2018; 9:1602-1616. https://doi.org/10.18632/oncotarget.20308

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Abstract

Janice M. Santiago-O’Farrill1, Eugenie S. Kleinerman1, Mario G. Hollomon2, Andrew Livingston3, Wei-Lien Wang4, Jen-Wei Tsai4 and Nancy B. Gordon1

1 Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

2 Department of Biology, Texas Southern University, Houston, Texas, USA

3 Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

4 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Correspondence to:

Nancy B. Gordon, email:

Keywords: osteosarcoma, autophagy, gemcitabine, hydroxychloroquine, Beclin

Received: October 20, 2016 Accepted: May 19, 2017 Published: August 17, 2017

Abstract

Autophagy is a catabolic process involved in cellular homeostasis. Autophagy is increased above homeostatic levels by chemotherapy, and this can either promote or inhibit tumor growth. We previously demonstrated that aerosol gemcitabine (GCB) has a therapeutic effect against osteosarcoma (OS) lung metastases. However, some tumor cells failed to respond to the treatment and persisted as isolated lung metastasis. Here, we examined the mechanisms underlying the dual role of chemotherapy-induced autophagy in OS and sought to identify biomarkers to predict OS response to treatment. In this study, we demonstrate that treatment of various OS cells with GCB induced autophagy. We also showed that GCB reduces the phosphorylation of AKT, mTOR and p70S6K and that GCB-induced autophagy in OS can lead to either cell survival or cell death. Blocking autophagy enhanced the sensitivity of LM7 OS cells and decreased the sensitivity of CCH-OS-D and K7M3 OS cells to GCB. Using a kinase array, we also demonstrated that differences in the phosphorylated heat shock protein 27 (p-HSP27) expression in the various OS cell lines after treatment with GCB, correlates to whether chemotherapy-induced autophagy will lead to increase or decrease OS cells sensitivity to therapy. Increased p-HSP27 was associated with increased sensitivity to anticancer drug treatment when autophagy is inhibited. The results of this study reveal a dual role of autophagy in OS cells sensitivity to chemotherapy and suggest that p-HSP27 could represent a predictive biomarker of whether combination therapy with autophagy modulators and chemotherapeutic drugs will be beneficial for OS patients.


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