Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

Abstract

Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin-associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA-I1 is most potent. The purposes of this study were to further investigate the effects of targeting PCNA chromatin association on DNA damage and cytotoxicity and to evaluate the therapeutic potential of PCNA-I1 against tumors in mice. Given the important roles of tumor suppressor p53 in regulating sensitivity of tumor cells to chemotherapeutics, we performed studies in two human prostate cancer cell lines differing in p53 expression: LNCaP cells (wild-type p53) and PC-3 cells (p53-null). PCNA-I1 induced DNA damage and apoptosis in both LNCaP and PC-3 cells and enhanced DNA damage and apoptosis triggered by cisplatin. PCNA-I1 also induced autophagy in PC-3 cells. A short-term pretreatment with PCNA-I1 reduced colony formation by 50% in both cell lines. These data suggest that, unlike many other cytotoxic drugs, the effects of PCNA-I1 on tumor cells do not depend on expression of p53. Intravenous administrations of PCNA-I1 significantly retarded growth of LNCaP tumors of in nude mice without causing detectable effects on mouse body weight and hematology profiles. These data provide proof of concept that targeting PCNA chromatin association could be a novel and effective therapeutic approach for treatment of cancer. Mol Cancer Ther; 13(12); 2817-26. Ó2014 AACR.

Long‐term oral exposure to safe dose of bisphenol A in association with high‐fat diet stimulate the prostatic lesions in a rodent model for prostate cancer

“…Through some markers commonly associated with neoplastic transformation in prostate tumors, we draw a phenotypic profile for injuries initiated by environmental factors used in this study. PCNA is an essential component of DNA replication and repair in the final common pathway shared by all mitogenic signals . In both lobes analyzed, PCNA rates increased significantly in the luminal epithelial cells, especially at sites of invasion.…”

TGF-β1 signaling pathway serves a role in HepG2 cell regulation by affecting the protein expression of PCNA, gankyrin, p115, XIAP and survivin

“…PCNA is a highly conserved protein; in addition to DNA replication, the functions of PCNA are associated with other vital cellular processes, including chromatin remodeling, DNA repair, sister-chromatid cohesion and cell cycle control (22). Recent studies have reported that tumor cells express increased levels of PCNA, identifying it as a potential target for cancer therapy (23,24). Gankyrin is a chaperone of the ubiquitin-proteasome and a novel oncogene, and has been demonstrated to be overexpressed in numerous types of cancer (25)(26)(27), including liver cancer (28)(29)(30), breast cancer (31,32), colorectal cancer (33), estrogen-driven endometrial carcinoma (26) and oral cancer (34).…”

ECRG2 enhances the anti-cancer effects of cisplatin in cisplatin-resistant esophageal cancer cells via upregulation of p53 and downregulation of PNCA

“…Dillehay et al[19] reported a novel small molecule targeting PCNA-induced DNA damage and apoptosis in prostate cancer cells, as well as enhancing DNA damage and apoptosis triggered by DDP in a p53-independent manner. Expression of PCNA genes in all organisms is traditionally associated with cell proliferation and thus with DNA synthesis during genome replication in the S phase of the cell cycle[20].…”

“…Both peptides and small molecules targeting PCNA signaling have been reported to sensitize cancer cells to chemotherapeutic agents[22,23]. A PCNA inhibitor can increase DNA double-strand breaks and cause the accumulation of DNA damage, which will eventually lead to cell death in cells that lack the ability to repair this damage[19]. In the present study, we demonstrated that the small molecule ECRG2 combined with DDP reversed DDP resistance by downregulating PCNA expression in esophageal DDP-resistant cancer cells.…”