Abstract 538: ASPM promotes prostate cancer tumorigenesis by bolstering cancer stemness through Wnt-Dvl-3-b-catenin signaling

Abstract

Metastasis is the major cause of cancer mortality in androgen-independent prostate cancer (PCA) and understanding it is crucial to improving the outcome of patients. Recent evidence suggests that activation of Wnt signaling in cancer stem cells (CSCs) contributes to cancer progression in malignant tumors. Here we report that a novel Wnt activator ASPM (Abnormal spindle-like microcephaly associated) maintains the prostate CSC subpopulation through augmenting the Wnt-β-catenin signaling in PCA. Functional studies showed that downregulation of ASPM expression attenuated the proliferation and invasive of PCA cells and reduced the number of prostate CSCs and inhibited cancer stemness and tumorigenesis. Mechanistically, ASPM interacts with dishevelled-3 (Dvl-3) and inhibits its proteasome-dependent degradation, thereby increasing the protein stability of Dvl-3 and enabling the β-catenin transcriptional activity in PCA cells. The clinical significance of the above findings was credentialed by the profound up-regulation of ASPM in metastatic PCA and the strong correlation of cytoplasmic ASPM expression with poor metastasis-free survival of patients with resected PCA. Collectively, our data points to ASPM as a novel oncoprotein and an essential regulator of cancer stemness in PCA, which has important clinical and therapeutic significance (supported by Ministry of Science and Technology grants MOST 104-2314-B-400-022 and MOST 105-2314-B-400-018 and National Health Research Institutes NHRIs grant CA-106-PP-09 to K.K.T). Citation Format: Kelvin K. Tsai, Vincent C. Pai, Chung-Chi Hsu, Tze-Sian Chan. ASPM promotes prostate cancer tumorigenesis by bolstering cancer stemness through Wnt-Dvl-3-b-catenin signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 538.

SPAG5 and ASPM play important roles in gastric cancer: An observational study

“…[33] ASPM plays multiple roles in mitosis, cell cycle progression, and DNA double-strand break repair, with tumorigenic ASPM serving as a regulatory hub for development and signaling in cancer. [34] ASPM has synergistic effects with PARP inhibition in killing tumor cells, making it a potential new target for lethal tumor combination therapy. [35] Whole-genome analysis reveals that upregulation of ASPM is associated with gastric cancer, and the E2F1-ASPM axis may represent a new mechanism for gastric cancer occurrence.…”