Purpose: Marine triterpene glycosides that are physiologically active natural compounds isolated from sea cucumbers (holothurians) and sponges have antifungal, cytotoxic, and antitumor activities, whose specific molecular mechanisms remain to be elucidated. In this study, we examined if and through which mechanisms stichoposide C (STC) from Thelenota anax (family Stichopodidae) induces apoptosis in leukemia and colorectal cancer cells.Experimental Design: We examined STC-induced apoptosis in human leukemia and colorectal cancer cells in the context of mitochondrial injury and signaling pathway disturbances, and investigated the antitumor effect of STC in mouse CT-26 subcutaneous tumor and HL-60 leukemia xenograft models.Results: We found that STC induces apoptosis in these cells in a dose-dependent manner and leads to the activation of Fas and caspase-8, cleavage of Bid, mitochondrial damage, and activation of caspase-3. STC activates acid sphingomyelinase (SMase) and neutral SMase, which resulted in the generation of ceramide. Specific inhibition of acid SMase or neutral SMase and siRNA knockdown experiments partially blocked STC-induced apoptosis. Moreover, STC markedly reduced tumor growth of HL-60 xenograft and CT-26 subcutaneous tumors and increased ceramide generation in vivo.Conclusions: Ceramide generation by STC, through activation of acid and neutral SMase, may in part contribute to STC-induced apoptosis and antitumor activity. Thus, STC may have therapeutic relevance for human leukemia and colorectal cancer. Clin Cancer Res; 18(21); 5934-48. Ó2012 AACR.

Peroxisome proliferator-activated receptor γ (PPARγ) is part of a nuclear receptor superfamily that regulates gene expression involved in cell differentiation, proliferation, immune/inflammation response, and lipid metabolism. PPARγ coactivator-1α (PGC-1α), initially identified as a PPARγ-interacting protein, is an important regulator of diverse metabolic pathways, such as oxidative metabolism and energy homeostasis. The role of PGC-1α in diabetes, neurodegeneration, and cardiovascular disease is particularly well known. PGC-1α is also now known to play important roles in cancer, independent of the role of PPARγ in cancer. Though many researchers have studied the expression and clinical implications of PPARγ and PGC-1α in cancer, there are still many controversies about the role of PPARγ and PGC-1α in cancer. This review examines and summarizes some recent data on the role and action mechanisms of PPARγ and PGC-1α in cancer, respectively, particularly the recent progress in understanding the role of PPARγ in several cancers since our review was published in 2012.

Abstract. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a coactivator interacting with multiple transcription factors, regulates several metabolic processes. Although recent studies have focused on the role of PGC-1α in cancer, the underlying molecular mechanism has not been clarified. Therefore, we evaluated the role of PGC-1α in cell proliferation and tumorigenesis using human embryonic kidney (HEK)293 cells and colorectal cancer cells. We established stable HEK293 cell lines expressing PGC-1α and examined cell proliferation, anchorage-independent growth, and oncogenic potential compared to parental HEK293 cells. To identify the molecular PGC-1α targets for increased cell proliferation and tumorigenesis, the GeneFishing™ DEG (differentially expressed genes) screening system was used. Western blot analysis and immunofluorescence staining were performed for a regulated gene product to confirm the results. Forced expression of PGC-1α in HEK293 cells promoted cell proliferation and anchorage-independent growth in soft agar. In addition, HEK293 cells that highly expressed PGC-1α showed enhanced tumor formation when subcutaneously injected into the bilateral flanks of immunodeficient mice. The results of the GeneFishing DEG screening system identified one upregulated gene (Acyl-CoA binding protein; ACBP). Real-time RT-PCR, western blot analysis, and immunofluorescence staining showed that ACBP was markedly increased in HEK293 cells stably overexpressing PGC-1α (PGC-1α-HEK293 cells) compared to those expressing an empty vector. In PGC-1α, ACBP, and specificity protein 1 (Sp1) siRNA knockdown experiments in PGC-1α-HEK293 and SNU-C4 cells, we also observed inhibition of cell proliferation, reduced expression of antioxidant enzymes, and increased H 2 O 2 -induced reactive oxygen species production and apoptosis. These findings suggest that PGC-1α may promote cell proliferation and tumorigenesis through upregulation of ACBP. We provide evidence that increased Sp1 expression might contribute to enhanced ACBP expression by PGC-1α. The current results also suggest that PGC-1α, whose expression is related to enhanced cell proliferation and tumorigenesis, may be a good candidate molecular target for cancer therapy.