Abstract
Hypoxia-adapted cancer cells in tumors contribute to the pathological progression of cancer. The marine spongean sesquiterpene phenols dictyoceratin-A (1) and -C (2) have been shown to induce hypoxia-selective growth inhibition in cultured cancer cells and exhibit in vivo antitumor effects. These compounds inhibit the accumulation of hypoxia-inducible factor-1α (HIF-1α), which is a drug target in hypoxia-adapted cancer cells, under hypoxic conditions. However, the target molecules of compounds 1 and 2, which are responsible for decreasing HIF-1α expression under hypoxic conditions, remain unclear. In this study, we synthesized probe molecules for compounds 1 and 2 to identify their target molecules and found that both compounds bind to RNA polymerase II-associated protein 3 (RPAP3), which is a component of the R2TP/Prefoldin-like (PEDL) complex. In addition, RPAP3-knockdown cells showed a phenotype similar to that of compound-treated cells.
Highlights
In tumors, the hypoxic environment is an important factor for tumor growth, angiogenesis, metastasis, and response to chemotherapy and irradiation
In order to identify the target molecules of dictyoceratin-A (1) and -C (2) as selective growth inhibitors of cancer cells adapted to hypoxic environments, we synthesized three types of probe inhibitors of cancer cells adapted to hypoxic environments, we synthesized three types of probe molecules (3–5) based on an analysis of structure-activity relationships using synthetic analogs of 1 molecules (3–5) based on an analysis of structure-activity relationships using synthetic analogs of 1 and and 2 (Figure 1 and Scheme S1) [13]
-C (2)of interacted with RNA polymerase II-associated protein 3 (RPAP3) in DU145 cells, we investigated the effects of dictyoceratin-A (1) on the growth of RPAP3-overexpressing cells, we investigated the effects of dictyoceratin-A (1) on the growth of RPAP3-overexpressing DU145
Summary
The hypoxic environment is an important factor for tumor growth, angiogenesis, metastasis, and response to chemotherapy and irradiation. Tumor cells in the hypoxic environment show resistance to chemotherapy and irradiation and enhancement of angiogenesis [1]. The hypoxic environment in a tumor is unlike that in normal tissues. Compounds that selectively inhibit the growth of tumor cells under hypoxic conditions are expected to have potential applications as anticancer drugs. The heterodimeric transcription factor hypoxia-inducible factor (HIF)-1, which comprises an oxygen-regulated α-subunit and a constitutively expressed β-subunit, is a well-studied regulator of cellular response to hypoxia. Decreased HIF-1 activity is usually associated with a slower growing and less angiogenic tumor phenotype [2]. HIF-1, HIF-1α, has been extensively studied as a potential drug target for cancer chemotherapy
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