Abstract 1654: Cisplatin resistance is associated with autophagy in SPARC expressing medulloblastoma cells.

Abstract Medulloblastoma is the most common malignant brain tumor in children and is associated with a poor outcome. Our previous studies indicate that SPARC expression suppressed medulloblastoma tumor growth in vitro and in vivo. We were interested in gaining further insight into the potential of SPARC expression as a novel approach to sensitize medulloblastoma to chemotherapeutic agents. In this study, we demonstrate that SPARC: expression resulted in enhanced resistance of cancer cells to cisplatin, a commonly used chemotherapeutic drug in the treatment of medulloblastoma. We also demonstrate that autophagy was involved in SPARC expression mediated resistance to cisplatin. We further demonstrated that suppression of autophagy by autophagy inhibitors, 3-methyladenosine (3MA) and small interfering RNAs (siRNAs) targeting Atg5 in SPARC expressed cells enhanced the sensitivity of medulloblastoma cells to cisplatin compared to cells treated with cisplatin alone. Moreover, sensitization to cisplatin by inhibition of autophagy is SPARC expressed cells was accompanied by induction of apoptosis indicating that suppression of autophagy indeed renders tumor cells more sensitive to cisplatin. Further we show overexpression of High mobility group box 1 (HMGB1 in SPARC expressed cells rendered medulloblastoma cells resistant to cell death; whereas depletion of HMGB1 using RNA interference suppressed autophagy and increased the sensitivity of medulloblastoma cells to cisplatin as assessed by microtubule-associated protein 1 light chain 3 (LC3) lipidation, redistribution of LC3 into cytoplasmic puncta, and accumulation of autophagosomes and autolysosomes. Further our data suggest a role for HMGB1 in the regulation of autophagy through the MEK-ERK pathway in SPARC over expressed cells. The results of our study revealed a new mechanism for enhancing cisplatin sensitivity in SPARC expressed cells. These findings have important clinical implications for the design of experimental treatment protocols for medulloblastoma. Citation Format: Padmavathi Pannuru, Ranadheer Dontula, Herbert Engelhard, Howard Ozer, Sajani S. Lakka. Cisplatin resistance is associated with autophagy in SPARC expressing medulloblastoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1654. doi:10.1158/1538-7445.AM2013-1654 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.