Exploring the Control of PARP1 Levels in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) is a leading cause of mortality from gynecologic malignancies worldwide. Although a transformative improvement has been shown with the introduction of PARP (poly(ADP-ribose) polymerase) inhibitors, the emergence of resistance to these drugs represents a therapeutic challenge. Hence, expanding our understanding of mechanisms behind the control of PARP1 expression can provide strategic guidance for the translation of novel therapeutic strategies.

Stat1 confers sensitivity to radiation in cervical cancer cells by controlling Parp1 levels: a new perspective for Parp1 inhibition.

Cervical cancer (CC) is the fourth most common cause of cancer-related death in women. According to international guidelines, a standard treatment for locally advanced cervical cancer (LACC) consists of exclusive concurrent chemoradiation treatment (CRT). However, chemoradioresistance and subsequent relapse and metastasis of cancer occur in many patients, and survival for these women has generally remained poor.

Clinical Value of lncRNA MEG3 in High-Grade Serous Ovarian Cancer.

Long non-coding RNAs (lncRNAs) are emerging as regulators in cancer development and progression, and aberrant lncRNA profiles have been reported in several cancers. Here, we evaluated the potential of using the maternally expressed gene 3 (MEG3) tissue level as a prognostic marker in high-grade serous ovarian cancer (HGSOC), the most common and deadliest gynecologic malignancy. To the aim of the study, we measured MEG3 transcript levels in 90 pre-treatment peritoneal biopsies.

A combined ANXA2-NDRG1-STAT1 gene signature predicts response to chemoradiotherapy in cervical cancer.

Background: A better understanding of locally advanced cervical cancer (LACC) is mandatory for further improving the rates of disease control, since a significant proportion of patients still fail to respond or undergo relapse after concurrent chemoradiation treatment (CRT), and survival for these patients has generally remained poor.

Methods: To identify specific markers of CRT response, we compared pretreatment biopsies from LACC patients with pathological complete response (sensitive) with those from patients showing macroscopic residual tumor (resistant) after neoadjuvant CRT, using a proteomic approach integrated with gene expression profiling. The study of the underpinning mechanisms of chemoradiation response was carried out through in vitro models of cervical cancer.

Preoperative Anti-Class III β-Tubulin Antibodies As Relevant Clinical Biomarkers in Ovarian Cancer.

Class III β-tubulin (TUBB3) overexpression in ovarian cancer (OC) associates with poor prognosis. We investigated whether TUBB3 overexpression elicited anti-TUBB3 antibody production in OC patients and whether these antibodies may have diagnostic and prognostic impact. The presence of serum anti-TUBB3 antibodies was investigated in 49 untreated OC patients and 44 healthy individuals by an in-house developed ELISA that used recombinant TUBB3 as the antigen.

Nek6 and Hif-1α cooperate with the cytoskeletal gateway of drug resistance to drive outcome in serous ovarian cancer.

Hypoxia selects the most aggressive and drug-resistant clones in solid malignancies. One of the pivotal transcription factors induced by hypoxia is Hif-1α. However, in serous ovarian cancer (SEOC), Hif-1α expression is not a prognostic biomarker.

Role and prognostic significance of the epithelial-mesenchymal transition factor ZEB2 in ovarian cancer.

ZEB2 is a key factor in epithelial-mesenchymal transition (EMT), a program controlling cell migration in embryonic development and adult tissue homeostasis. We demonstrated a role of ZEB2 in migration and anchorage-independent cell growth in ovarian cancer, as shown by ZEB2 silencing. We found that the RNA-binding protein HuR bound the 3'UTR of ZEB2 mRNA, acting as a positive regulator of ZEB2 protein expression.

Sox9 and Hif-2α regulate TUBB3 gene expression and affect ovarian cancer aggressiveness.

Unlabelled: SOX9 [(sex determining region Y)-box9] gene has been implicated in the development and progression of different neoplasms. This study investigated the role of Sox9 in the expression of TUBB3 gene, a marker of aggressiveness in ovarian cancer (OC), encoding βIII-tubulin protein. Gene expression was assessed by quantitative polymerase chain reaction (qPCR) in OC models.

MiR-200c and HuR in ovarian cancer.

Background: MicroRNAs in solid malignancies can behave as predictors of either good or poor outcome. This is the case with members of the miR-200 family, which are the primary regulators of the epithelial to mesenchymal transition and have been reported to act as both oncogenes and tumor suppressors. This study assessed the role of miR-200c as regulator of class III β-tubulin (TUBB3), a factor associated with drug-resistance and poor prognosis in ovarian cancer.

Gli family transcription factors are drivers of patupilone resistance in ovarian cancer.

Epothilones constitute a novel class of antitubulin agents that are active in patients who relapse after treatment with other chemotherapeutics. This study investigated the molecular mechanisms leading to the onset of epothilone-B (patupilone) resistance in ovarian cancer. Results demonstrated that the Gli family of transcription factors was overexpressed in resistant cells and that treatment with a specific Gli1 inhibitor (GANT58) made cells more susceptible to treatment, partially reversing drug resistance.

RON and cisplatin resistance in ovarian cancer cell lines.

RON (recepteur d'origine nantais) tyrosine kinase receptor has revealed its tumorigenic potential in recent studies. RON was reported to be overexpressed in 55% of primary ovarian carcinoma samples and furthermore its activation increases cell motility and invasiveness. In this study, we investigated the correlation between RON expression and chemoresistance in ovarian cancer cells.

HuR regulates beta-tubulin isotype expression in ovarian cancer.

The supply of oxygen and nutrients to solid tumors is inefficient because cancer tissues have an inadequate number of microvessels, thus inducing the selective growth of the most aggressive cancer cells. This explains why many of the factors underlying a poor prognosis are induced in hypoxic/hypoglycemic conditions. Among these factors, a prominent role in several solid tumors is played by the class III beta-tubulin gene (TUBB3).

Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77.

We reported previously that Bcl-2 is paradoxically down-regulated in paclitaxel-resistant cancer cells. We reveal here that paclitaxel directly targets Bcl-2 in the loop domain, thereby facilitating the initiation of apoptosis. Molecular modeling revealed an extraordinary similarity between the paclitaxel binding sites in Bcl-2 and beta-tubulin, leading us to speculate that paclitaxel could be mimetic of an endogenous peptide ligand, which binds both proteins.

Antiproliferative and antiangiogenic effects of the benzophenanthridine alkaloid sanguinarine in melanoma.

This study was aimed at evaluating the potential application of benzophenanthridine alkaloids, sanguinarine and cheleritrine, in the therapy of melanoma cancer. In vitro antiproliferative activity of sanguinarine was higher than that of cheleritrine against the B16 melanoma 4A5 cells. Both agents were able to produce DNA breaks, and the DNA unwinding assay showed that they act as DNA intercalating agents.

Looking at drug resistance mechanisms for microtubule interacting drugs: does TUBB3 work?

Vinca alkaloids and taxanes represent the mainstay of medical treatment of hematological and solid tumors. Unfortunately, a major clinical problem with these agents is drug resistance. Although a plethora of mechanisms of drug resistance have been described, only a few of them have been validated in clinical trials.

From plasma membrane to cytoskeleton: a novel function for semaphorin 6A.

Class III beta-tubulin (TUBB3) overexpression has been reported in ovary, lung, breast, and gastric cancer patients. Currently, no clinical drugs are available for a specific targeting of TUBB3, whereas the investigational drug IDN5390 specifically interacts with TUBB3. To gain insight into the pathways leading to TUBB3 up-regulation, we did a human genome microarray analysis in A2780 cells made resistant to IDN5390 to identify selected pathways specifically disrupted in resistant cells.

Hypoxia induces class III beta-tubulin gene expression by HIF-1alpha binding to its 3' flanking region.

Class III beta-tubulin (TUBB3) overexpression represents a major mechanism of drug resistance to microtubule interacting agents such as taxanes and Vinca alkaloids. Here, we tested hypoxia as a possible inducer of TUBB3. The effects of hypoxia on TUBB3 expression were monitored at mRNA and protein level in A2780, in its paclitaxel-resistant counterpart (TC1) and in HeLa cells.

Bcl-2 down-regulation and tubulin subtype composition are involved in resistance of ovarian cancer cells to vinflunine.

Vinflunine, a new microtubule-targeting drug, has a marked antitumor activity in vitro and in vivo. Here, we studied the mechanisms mediating resistance to vinflunine. We investigated the response to vinflunine of ovarian cancer cells initially selected as paclitaxel-resistant cells (A2780-TC1 cells).

Microsatellite instability is not related to response to cisplatin-based chemotherapy in cervical cancer.

This study investigates whether microsatellite instability (MSI) due to defects of the mismatch repair (MMR) system could be associated with response to cisplatin-based neoadjuvant chemotherapy (NACT) and if cisplatin exposure could select MSI-positive cell clones in cervical cancer. Microsatellite analysis was performed by polymerase chain reactions using six microsatellite markers, while hMLH1 protein expression was investigated by immunohistochemistry. We found that 1 tumor out of 20 (5%) NACT-responding patients and 1 tumor out of 18 (6%) nonresponding patients showed MSI.

The seco-taxane IDN5390 is able to target class III beta-tubulin and to overcome paclitaxel resistance.

A prominent mechanism of drug resistance to taxanes is the overexpression of class III beta-tubulin. The seco-taxane IDN5390 was chosen for its selective activity in paclitaxel-resistant cells with an overexpression of class III beta-tubulin. Moreover, the combined treatment paclitaxel/IDN5390 yielded a strong synergism, which was also evident in cell-free tubulin polymerization assays.

Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients.

The vast majority of women with advanced ovarian cancer will ultimately relapse and develop a drug-resistant disease with an overall 5-year survival of <50%. Unfortunately, the mechanisms of drug resistance actually operating in patients are still unknown. To address this issue, in 41 patients affected by advanced ovarian cancer the three main mechanisms of paclitaxel resistance were investigated: overexpression of MDR-1 gene, point mutations at prominently expressed alpha-tubulin and beta-tubulin genes and selective alterations in the expression of beta-tubulin isotypes.

Thiocolchicine dimers: a novel class of topoisomerase-I inhibitors.

During a cellular screening of thiocolchicine analogs, thiocolchicine dimers resulted particularly active in cisplatin-resistant A2780-CIS cells. In order to discover by which mechanism(s) thiocolchicine dimers overcame cisplatin resistance, p53, p21waf1 and MLH1 were assessed by Western blot. Results pointed out that, when combined with cisplatin, dimers increased the amount of all the three proteins with respect to the levels obtained by single drug exposure, thereby suggesting an interference in the process of repair of the cisplatin-induced DNA lesions.

Epidermal growth factor-responsive laryngeal squamous cancer cell line Hep2 is more sensitive than unresponsive CO-K3 one to quercetin and tamoxifen apoptotic effects.

Epidermal growth factor receptor (EGFR) plays a role in laryngeal squamous cell carcinoma (SCC) development and progression. The flavonoid quercetin (Q) and the antiestrogen tamoxifen (TAM) inhibit proliferation of both primary laryngeal SCC and laryngeal carcinoma cell lines, through still uncharacterized mechanisms. We studied Q and TAM inhibitory effect on epidermal growth factor (EGF)-stimulated Hep2 and CO-K3 laryngeal squamous cell lines.