Abstract 358: The role of GDF-15 on docetaxel resistance in lung cancer
Authors: Watanabe Mototsugu , Masada Yasutaka , Hashida Shinsuke , Ohtsuka Tomoaki , Suzawa Ken , Maki Yuho , Yamamoto Hiromasa , Soh Junichi , Asano Hiroaki , Tsukuda Kazunori , Toyooka Shinichi , Miyoshi Shinichiro 
Published: August 2015

[Background] Lung cancer is the leading cause of cancer death in many countries. One of major reasons for poor prognosis is that lung cancer reveals resistance to therapeutic drugs. Thus, it is important to elucidate the mechanisms of resistance to drugs. Growth differentiation factor-15 (GDF-15) is the member of the transforming growth factor-β superfamily, and it shows multiple functions such as control of development, anti-inflammation, immunosuppression. In prostate cancer cell, it is reported that GDF-15 are related to cancer progression, survival, recurrence, and chemo-resistance. In this study, we examined the roles of GDF-15 in lung cancer, especially about chemo-resistance.

[Materials and Methods] We used three lung cancer cell lines (HCC4006, HCC4006-DR which acquired docetaxel (DOC) resistance after long term exposure for DOC with stepwise manner, and A549), a non-malignant immortalized fibroblast cell (OUMS-24), and two non-malignant immortalized bronchial epithelial cells (HBEC-5KT and BEAS-2B). We also used lung cancer-associated fibroblast (CAF) and normal fibroblast which were established by primary culture of surgically resected lung cancer tissue and corresponding distant normal lung tissue from two patients, respectively. A quantitative reverse transcriptional real time PCR assay were performed to quantify GDF-15 mRNA expression. Apoptosis were evaluated by cleaved caspase-3 assay. The MTS assay was performed to calculate IC50 values for DOC.

[Results] GDF-15 mRNA expression level was very low in parental HCC4006 but high in HCC4006-DR and moderate in A549. After DOC treatment, GDF-15 expression was highly upregulated in a fibroblast cell (OUMS-24) but not in HBEC-5KT and BEAS-2B. Furthermore, upregulation of GDF-15 expression after DOC treatment was more highly promoted in two CAFs than corresponding normal fibroblasts. DOC treatment induced apoptosis in HCC4006, but DOC-induced apoptosis was inhibited by injection of DOC protein. In addition, sensitiveness for DOC was also inhibited by injection of DOC protein.

[Conclusion] DOC treatment promotes upregulation of GDF-15 expression especially in CAFs. Secreted GDF-15 inhibits DOC-induced apoptosis and sensitiveness for DOC treatment. These facts suggest that GDF-15, which is highly produced by CAFs, may play an important role of DOC resistance in lung cancer.

Citation Format: Mototsugu Watanabe, Yasutaka Masada, Shinsuke Hashida, Tomoaki Ohtsuka, Ken Suzawa, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichi Toyooka, Shinichiro Miyoshi. The role of GDF-15 on docetaxel resistance in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 358. doi:10.1158/1538-7445.AM2015-358