A novel selenonucleoside suppresses tumor growth by targeting Skp2 degradation in paclitaxel-resistant prostate cancer

Woong Sub Byun; Minkyung Jin; Jinha Yu; Won Kyung Kim; Jayoung Song; Hwa-Jin Chung; Lak Shin Jeong; Sang Kook Lee

doi:10.1016/j.bcp.2018.10.002

A novel selenonucleoside suppresses tumor growth by targeting Skp2 degradation in paclitaxel-resistant prostate cancer

Biochem Pharmacol. 2018 Dec:158:84-94. doi: 10.1016/j.bcp.2018.10.002. Epub 2018 Oct 5.

Authors

Woong Sub Byun¹, Minkyung Jin¹, Jinha Yu², Won Kyung Kim¹, Jayoung Song¹, Hwa-Jin Chung¹, Lak Shin Jeong², Sang Kook Lee³

Affiliations

¹ College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
² College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
³ College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: sklee61@snu.ac.kr.

PMID: 30292755
DOI: 10.1016/j.bcp.2018.10.002

Abstract

Prostate cancer (PC) is the most common disease in men over age 50, and its prevalence rate has been gradually increasing since 1980. Taxane-derived anticancer agents are the primary agents used to treat metastatic prostate cancer patients; however, the side effects and acquired drug resistance limit the success of these therapies. Because there is no specific treatment for paclitaxel-resistant prostate cancer, it is necessary to develop new targets and therapeutic strategies to overcome the acquired resistance. In this study, the antitumor activity of a novel selenonucleoside (4'-selenofuranosyl-2,6-dichloropurine, LJ-2618), a third-generation nucleoside, and its plausible mechanisms of action in paclitaxel-resistant prostate cancer (PC-3-Pa) cells were investigated. The established PC-3-Pa cells exhibited over 100-fold resistance against paclitaxel compared to the paclitaxel-sensitive PC-3 cells. LJ-2618, however, effectively inhibited the proliferation of both cell lines with similar IC₅₀ values in vitro. In PC-3-Pa cells, the activated PI3K/Akt signaling pathway was suppressed by LJ-2618 treatment. In addition, Skp2 was found to be over-expressed in paclitaxel-resistant cells, and the transfection of Skp2 siRNA recovered the sensitivity of paclitaxel in PC-3-Pa cells. Furthermore, LJ-2618 significantly down-regulated Skp2 expression in PC-3-Pa cells by promoting degradation and inducing destabilization of Skp2, which triggers G₂/M cell cycle arrest. In a xenograft mouse model implanted with PC-3-Pa cells, LJ-2618 (3 or 10 mg/kg) effectively inhibited tumor growth with the enhancement of Skp2 degradation and induction of p27 expression in tumor tissues. These findings suggest that LJ-2618 may have potential for overcoming paclitaxel resistance via promoting Skp2 degradation and stabilizing p27 expression in PC-3-Pa cells. Therefore, the novel selenonucleoside LJ-2618 may lead to the development of a new treatment strategy for patients with paclitaxel-resistant, castration-resistant prostate cancer.

Keywords: A novel selenonucleoside LJ-2618; G(2)/M cell cycle; P27; Paclitaxel-resistant prostate cancer; Skp2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Phytogenic / administration & dosage*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Proliferation / physiology
Drug Delivery Systems / methods*
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / physiology
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Paclitaxel / administration & dosage*
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
S-Phase Kinase-Associated Proteins / antagonists & inhibitors
S-Phase Kinase-Associated Proteins / metabolism*
Xenograft Model Antitumor Assays / methods

Substances

Antineoplastic Agents, Phytogenic
S-Phase Kinase-Associated Proteins
SKP2 protein, human
Paclitaxel