Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer

Abstract

Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the bric-a-brac-tramtrack-broad complex/pox virus and zinc finger gene family, is known to serve important roles in the proliferation and growth of tumor cells, and in chemotherapy resistance. However, the underlying molecular mechanisms through which NAC1 contributes to drug resistance remain unclear. In the present study, the role of NAC1 in drug resistance in ovarian cancer was investigated. NAC1 expression was markedly negatively associated with growth arrest and DNA-damage-inducible 45γ-interacting protein 1 (GADD45GIP1) expression in ovarian cancer. Increased NAC1 expression or decreased GADD45GIP1 expression was significantly associated with decreased progression-free survival (P=0.0041). Multivariate analysis demonstrated that NAC1/GADD45GIP1 expression was an independent prognostic factor of progression-free survival (P=0.0405). It was investigated whether cellular senescence was involved in NAC1-mediated resistance to cisplatin, a commonly used chemotherapeutic drug in the treatment of ovarian cancer. Treatment with cisplatin activated cellular senescence in ovarian cancer cell lines (SKOV3 and TOV-21G cells). Furthermore, knockdown of NAC1 by RNA interference significantly increased GADD45GIP1 expression and inhibited cisplatin-induced cellular senescence, resulting in increased cisplatin cytotoxicity in SKOV3 cells, which express increased levels of NAC1. To investigate whether the sensitizing effect of NAC1 inhibition on cisplatin-induced cytotoxicity may be attributed to the suppression of cellular senescence, the effects of NAC1 overexpression were assessed in TOV-21G cells, which do not express endogenous NAC1. Transfection with NAC1 in TOV-21G cells reduced the sensitivity of TOV-21G cells to cisplatin, indicating that suppression of cellular senescence was induced by GADD45GP1 activation. The results of the present study suggest that NAC1 is a negative regulator of cellular senescence and that NAC1-dependent suppression of senescence, mediated through GADD45GIP1, serves an important role in promoting cisplatin resistance. Therefore, the NAC1/GADD45GIP1 axis may be a potential target for the treatment of ovarian cancer, particularly in platinum-resistant cancers.

Transcriptome-based Stemness Indices Analysis Reveals Platinum-based Chemotheraputic Response Indicators in Advanced-stage Serous Ovarian Cancer

“…This con rmed the uncontrolled cell proliferation was a core characteristic of OC cells as well as the ovarian cancer stem cells (OVSCSs). In the results of the KEGG pathway, we found that the pathway "Cell cycle" [18,19], "Cellular senescence" [13][14][15], "p53 signaling pathway" [16,17], and "Platinum drug resistance" were closely associated with platinum sensitivity according to previous reports. A recent review had summarized that an insu cient dose of platinum might lead to a cytostatic response, named dormancy, rather than cytotoxic response, through inducing cell cycle arrest and cellular senescence [26].…”

“…These key genes were mainly involved in the pathways of the cell cycle ( Figure 3B). Interestingly, the selected key genes were also enriched to the platinum response-associated pathways "cellular senescence" [13][14][15], "p53 signaling pathway" [16,17], and "Platinum drug resistance" ( Figure 3B). Cell cycle arrest was also the main molecular mechanism of the platinum anticancer effect [18,19].…”

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

“…Platinum-based Cisplatin A375, B16F10, B16F10 xenografts SASP, SA-β-gal [64] A2780 SAHF (HP1-γ), morphology, SA-β-gal [68] CNE1 Growth arrest, morphology, SA-β-gal [30] SKOV3, TOV-21G Morphology, SA-β-gal [69] HepG2, SMMC-7721 SA-β-gal, p53, p21 Cip1 , p16 INK4 [70] Follicular lymphoma 3D model SA-β-gal [49] In vivo mouse model (p16-3MR) p16 INK4 [28] Carboplatin H1299, patients' lung tumor samples Cell cycle arrest, SA-β-gal, p16 INK4 , RB, downregulation of cyclin B1 and cyclin D1 [71] Oxaliplatin PROb, CT26 SA-β-gal [72] HepG2, SMMC-7721, patients' colorectal tumor samples SA-β-gal [73] Antimetabolites Methotrexate C85 p53 [74] C85 SA-β-gal [75] MCF-7 SA-β-gal [76] Rat-derived BMSCs and ADSCs SA-β-gal [42] A549 p21 Cip1 , low Ki67, growth arrest, SA-β-gal, increased granularity, morphology, SASP (IL-6, IL-8), γH2AX [43] SH-SY-5Y p21 Cip1 , growth arrest, SA-β-gal, γH2AX [43] HCT116 p21 Cip1 , low Ki67, growth arrest, SA-β-gal, increased granularity, morphology, SASP (IL-8), γH2AX [43] MDA-MB-231 p21 Cip1 , growth arrest, SA-β-gal, morphology, SASP (IL-6, IL-8, VEGF) [43] MCF-7 p21 Cip1 , low Ki67, growth arrest, SA-β-gal, increased granularity, morphology, γH2AX [43] Pemetrexed H1650, A549, H2228, H292, H226 and H1650, A549 xenografts SA-β-gal, morphology, SASP (IL-6, IL-8, IL-1β and MCP-1) [77] A549 SASP, SA-β-gal [78] Gemcitabine Miapaca-2 and Panc-1 SA-β-gal [79] AsPc1, Panc1 SA-β-gal [80] Azacitidine U2OS, MCF7 SA-β-gal, p53, growth arrest [81] TPC-1 SA-β-gal [82] KKU100, HuCCA1, RMCCA1 Morphology, SA-β-gal [83] DU145, LNCaP Morphology, growth arrest, polyploidy [40] Bromodeoxyuridine MNA, STA-NB-10, CLB-Ma mouse xenograft (MYCN-amplified neuroblastoma)…”

“…Cisplatin induces senescence in several melanoma cell lines associated with a vigorous secretory response [64]. Cisplatin also induces senescence in A2780, SKOV3 and TOV-21G ovarian cancer cells; A549 and H292 lung cancer cells; HepG2 and SMMC-7721 hepatocellular cancer cells and CNE1 nasopharyngeal cancer cells [30,[68][69][70]. In addition, carboplatin, a more tolerable cisplatin analogue, was shown to induce senescence in tumor samples obtained from non-small cell lung cancer patients who received carboplatin + docetaxel neoadjuvant therapy [71].…”

<p>MiR-218-5p Suppresses the Progression of Retinoblastoma Through Targeting NACC1 and Inhibiting the AKT/mTOR Signaling Pathway</p>

“…11 NACC1 not only regulates the tumorigenesis and development but also affects the therapeutic effect of chemotherapeutic drugs, causing a chemical resistance. [12][13][14][15] NACC1 knockdown inhibited the cisplatin-induced autophagy, resulting in increased cisplatin cytotoxicity. 13 NAC1 mediates cisplatin resistance by altering the High-mobility group box 1 (HMGB1)mediated autophagic response in ovarian cancer.…”