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

Prislei, Silvia; Mozzetti, Simona; Filippetti, Flavia; Donato, Marta De; Raspaglio, Giuseppina; Cicchillitti, Lucia; Scambia, Giovanni; Ferlini, Cristiano

doi:10.1158/1535-7163.mct-07-0390

Cited by 27 publications

(24 citation statements)

References 28 publications

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“…A2780 and OVCAR-3 human ovarian cancer cells were purchased from the European Collection of Cell Cultures (ECACC). TAX50, PTX, and TC1 cells are A2780 cells resistant to paclitaxel and are described elsewhere (8,9). Culture media were selected according to ECACC suggestions.…”

Section: Methodsmentioning

confidence: 99%

Molecular Mechanisms of Patupilone Resistance

et al. 2008

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Patupilone is an epothilone in advanced clinical development that has shown promising efficacy in heavily pretreated patients. This study aimed at characterizing the mechanisms of patupilone activity in resistant patients. To this end, we generated patupilone-resistant cells using two cellular models, the first characterized by high chemosensitivity and low class III B-tubulin (TUBB3) expression (A2780), and the second by low chemosensitivity and high TUBB3 expression (OVCAR-3). The obtained cell lines were named EPO3 and OVCAR-EPO, respectively. The same selection procedure was done in A2780 cells to generate a paclitaxel-resistant cell line (TAX50). Factors of resistance are expected to increase in the drugresistant cell lines, whereas factors of drug sensitivity will be down-regulated. Using this approach, we found up-regulation of TUBB3 in TAX50, but not EPO3, cells, showing that TUBB3 mediates the resistance to paclitaxel but not to patupilone. Moreover, TUBB3 was a factor of patupilone sensitivity because OVCAR-EPO cells exhibited a dramatic reduction of TUBB3 and a concomitant sensitization to hypoxia and cisplatin-based chemotherapy. To identify the mechanisms underlying patupilone resistance, tubulin genes were sequenced, thereby revealing that a prominent mechanism of drug resistance is represented by point mutations in class I B-tubulin. Overall, these results suggest that paclitaxel and patupilone have nonoverlapping mechanisms of resistance, thus allowing the use of patupilone for those patients relapsing after paclitaxel-based chemotherapy. Furthermore, patupilone represents a promising first-line option for the treatment of high-risk ovarian cancer patients, who exhibit high TUBB3 levels and poor response to standard paclitaxelplatin chemotherapy.

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Section: Methodsmentioning

confidence: 99%

Molecular Mechanisms of Patupilone Resistance

et al. 2008

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“…Biophysical studies have also indicated that BH3-domain proteins, of which Bim is a member, can interact with tubulin through this domain (227). The pro-survival factors semaphorin 6A and survivin also associate with microtubules (107, 229, 230) with the latter affecting microtubule dynamics (229). Semaphorin 6A interacts directly with βIII-tubulin in ovarian cancer cell lines and its expression correlates with resistance to a broad range of chemotherapy agents (230).…”

Section: Microtubule Cytoskeleton In Stress Responsesmentioning

confidence: 99%

Microtubules and Their Role in Cellular Stress in Cancer

2014

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Microtubules are highly dynamic structures, which consist of α- and β-tubulin heterodimers, and are involved in cell movement, intracellular trafficking, and mitosis. In the context of cancer, the tubulin family of proteins is recognized as the target of the tubulin-binding chemotherapeutics, which suppress the dynamics of the mitotic spindle to cause mitotic arrest and cell death. Importantly, changes in microtubule stability and the expression of different tubulin isotypes as well as altered post-translational modifications have been reported for a range of cancers. These changes have been correlated with poor prognosis and chemotherapy resistance in solid and hematological cancers. However, the mechanisms underlying these observations have remained poorly understood. Emerging evidence suggests that tubulins and microtubule-associated proteins may play a role in a range of cellular stress responses, thus conferring survival advantage to cancer cells. This review will focus on the importance of the microtubule–protein network in regulating critical cellular processes in response to stress. Understanding the role of microtubules in this context may offer novel therapeutic approaches for the treatment of cancer.

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“…The construct was prepared by Genscript. The control vector SiC not targeting any known gene was obtained as previously described using the same vector (12). Colo320 and SW480 cells were transfected using 2 mg DNA per 1 Â 10 6 cells.…”

Section: Stable Silencing Of Armentioning

confidence: 99%

“…Other primers were previously reported (13). To normalize the possible variation in sample concentration, we used glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as housekeeping control, as previously described (12). The results were analyzed using the REST software.…”

Section: Translational Relevancementioning

confidence: 99%

Gender Influences the Class III and V β-Tubulin Ability to Predict Poor Outcome in Colorectal Cancer

Mariani

Zannoni

Sioletic

et al. 2012

Clinical Cancer Research

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Purpose: Colorectal cancer is one of the deadliest diseases in Western countries. To predict the outcome of therapy, we assessed the role of class III (TUBB3) and class V b-tubulin (TUBB6) as predictive biomarkers.Experimental Design: Using immunohistochemistry and nanofluidics, the expression of TUBB3 and TUBB6 was assessed in two cohorts of 180 and 134 patients, respectively. The CYP17A1 RS743572 was genotyped to identify GG carriers with enhanced androgen levels. TUBB3 and TUBB6 were investigated in 22 colorectal cancer cell lines in basal conditions and after serum starvation, the latter serving as activator of this prosurvival pathway. To ascertain the role of androgen receptor (AR) in such regulation, we silenced AR and checked TUBB3 and TUBB6 expression and sensitivity to chemotherapy.Results: There was a link between poor survival, the expression of TUBB3/TUBB6, and AR only in females. Conversely, only in males carriers of the GG phenotype exhibited the worst outcome. Importantly, male cell lines were resistant to serum starvation and exhibited higher levels of TUBB6, thereby suggesting that the pathway is activated by androgens. In female cells this phenomenon was absent. In both genders, AR was the main driver of TUBB3/TUBB6 expression, as constitutive silencing of AR was associated with downregulation of TUBB3/TUBB6 expression and increased sensitivity to oxaliplatin and SN-38.Conclusions: The involvement of androgens in the TUBB3 pathway opens the way for clinical trials to assess the efficacy of antiandrogens for increasing the efficacy of chemotherapy in male colorectal cancer patients.

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

Cited by 27 publications

References 28 publications

Molecular Mechanisms of Patupilone Resistance

Molecular Mechanisms of Patupilone Resistance

Microtubules and Their Role in Cellular Stress in Cancer

Gender Influences the Class III and V β-Tubulin Ability to Predict Poor Outcome in Colorectal Cancer

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