Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells

Romano, Simona; Dilhas, Anna; Pacelli, Roberto; Staibano, S.; Luna, Elvira De; Bisogni, Rita; Eskelinen, Eeva‐Liisa; Mascolo, Massimo; Calı̀, Gaetano; Arra, Claudio; Romano, Maria Fiammetta

doi:10.1038/cdd.2009.115

Cited by 116 publications

(166 citation statements)

References 35 publications

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“…Notably, inhibition of the autophagy signaling pathway by 3-MA significantly enhanced OX-induced cell apoptosis in vitro and tumor suppression in vivo, indicating that the activation of autophagy by OX may reduce OX cytotoxicity. The results of the current study are consistent with previous findings (17,18) and a recent report (14), in which cisplatin-induced autophagy reduced its apoptotic effect by downregulating the ER stress-mediated apoptosis pathway and the mitochondrial apoptosis pathway in HeLa cells. Considering the results of the present study, it is plausible that OX-activated autophagy may be responsible for the observed clinical inefficiency of OX in specific patients with colon cancer.…”

Section: Discussionsupporting

confidence: 83%

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Enhancement of oxaliplatin-induced cell apoptosis and tumor suppression by 3-methyladenine in colon cancer

Tan

Peng

et al. 2015

Oncology Letters

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Abstract. Oxaliplatin (OX) has been widely used in adjuvant and palliative treatments of advanced colon cancer; however, cancer cells ultimately become resistant in the majority of cases. Therefore, the development of a novel strategy to overcome this resistance is important for the effective treatment of colon cancer. Cell autophagy reduces the sensitivity of cancer cells to therapeutic reagents in various types of human cancer; therefore, the present study used murine CT26 colon carcinoma cells to explore whether inhibition of autophagy by 3-methyladenine (3-MA) is able to enhance OX-induced apoptosis in vitro and OX-suppressed tumor growth in vivo. CT26 cells were treated with 3-MA, OX, or 3-MA plus OX, and the autophagy, apoptosis and proliferation of the CT26 cells was investigated. Additionally, the therapeutic efficiency of the combination of 3-MA and OX treatment was evaluated in vivo by determining the survival time of the tumor-bearing mice and, thus, tumor growth rate. The treatment of CT26 cells in vitro with OX alone increased autophagy as well as apoptosis, whereas treatment with 3-MA plus OX markedly inhibited OX-induced autophagy, but increased OX-induced cell apoptosis. Furthermore, the combination of OX and 3-MA treatment significantly suppressed tumor growth in vivo and prolonged mouse survival time when compared with OX treatment alone. Similarly, 3-MA increased OX-induced cell apoptosis and decreased autophagy in xenograft tumor tissues. Thus, the administration of 3-MA may increase tumor cell sensitivity to OX by reducing its autophagic effects and enhancing its apoptotic effects. Data obtained in the present study indicates that the clinical combination of an autophagy inhibitor with OX may increase the therapeutic effect of OX and improve the clinical outcome of patients with colon cancer.

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Section: Discussionsupporting

confidence: 83%

“…It has previously been reported that the activation of autophagy in cancer cells inhibits therapy-induced apoptosis (17,18). In the current study, OX was observed to induce apoptosis as well as autophagy in CT26 cells.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of oxaliplatin-induced cell apoptosis and tumor suppression by 3-methyladenine in colon cancer

Tan

Peng

et al. 2015

Oncology Letters

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“…[7][8][9] On the other hand, some cancer cells can utilize activated autophagy to ameliorate deficiencies in nutrition and oxygen, caused by rapid fission and ischemia. [10][11][12] BECN1/Beclin1, an ortholog of Vps30/Atg6 in yeast, is a central component in autophagy and also plays crucial roles in development, tumorigenesis and neurodegeneration. 7 Interestingly, BECN1 was initially discovered not as an autophagy protein but rather as an interaction partner for the antiapoptotic protein BCL2.…”

Section: Introductionmentioning

confidence: 99%

GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3

Zhang

et al. 2015

Autophagy

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Abbreviations: ACTB/b-actin, actin, beta; ATG, autophagy-related, Baf, bafilomycin A 1 ; BECN1, Beclin 1, autophagy related; DAPI, 4 0 ,6-diamidino-2-phenylindol dihydrochloride; DNA, deoxyribose nucleic acid; GADD45A, growth arrest and DNA-damage-inducible, alpha; GFP, green fluorescent protein; GST, glutathione s-transferase; LC3/MAP1LC3, microtubule-associated protein 1 light chain 3; MEFs, mouse embryonic fibroblasts; MTOR, mechanistic target of rapamycin (serine/threonine kinase); PIK3C3, phosphatidylinositol 3-kinase, catalytic subunit type 3; RFP, red fluorescent protein; SDS, sodium dodecyl sulfate; SQSTM1, sequestosome 1; UVR, ultraviolet radiation GADD45A is a TP53-regulated and DNA damage-inducible tumor suppressor protein, which regulates cell cycle arrest, apoptosis, and DNA repair, and inhibits tumor growth and angiogenesis. However, the function of GADD45A in autophagy remains unknown. In this report, we demonstrate that GADD45A plays an important role in regulating the process of autophagy. GADD45A is able to decrease LC3-II expression and numbers of autophagosomes in mouse tissues and different cancer cell lines. Using bafilomycin A 1 treatment, we have observed that GADD45A regulates autophagosome initiation. Likely, GADD45A inhibition of autophagy is through its influence on the interaction between BECN1 and PIK3C3. Immunoprecipitation and GST affinity isolation assays exhibit that GADD45A directly interacts with BECN1, and in turn dissociates the BECN1-PIK3C3 complex. Furthermore, we have mapped the 71 to 81 amino acids of the GADD45A protein that are necessary for the GADD45A interaction with BECN1. Knockdown of BECN1 can abolish autophagy alterations induced by GADD45A. Taken together, these findings provide the novel evidence that GADD45A inhibits autophagy via impairing the BECN1-PIK3C3 complex formation.

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“…In a previous work, we provided evidence that targeting of FK506 binding protein 51 (FKBP51) with siRNA determined a significant apoptosis sensitizing effect of irradiated melanoma [5]. Our studies have highlighted a relevant role for FKBP51 in melanoma resistance to genotoxic agents [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

“…Our studies have highlighted a relevant role for FKBP51 in melanoma resistance to genotoxic agents [5][6][7]. To find out molecular targets for radiosensitizing strategies of melanoma, we investigated the changes of protein profiles in irradiated melanoma depleted or not of FKBP51, by protein microarray approach.…”

Section: Introductionmentioning

confidence: 99%

A Role for Proteomics in Identifying Targets for Radiosensitizing Strategies in Melanoma: The FKBP51 Paradigm

Dilhas¹,

Pacelli²,

Martinelli³

et al. 2014

J Proteomics Bioinform Vol.

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The treatment of metastatic melanoma is challenging and in the vast majority of cases unsuccessful. Melanoma cells are resistant to most standard therapeutics. We have recently demonstrated that FKBP51 regulates melanoma response to ionizing radiation (IR). To find out molecular targets for radiosensitizing strategies to apply in this neoplasm, we investigated the changes of protein profiles in irradiated melanoma depleted or not of FKBP51, by protein microarray approach. Among the multiple molecules that were found modulated in our cell model, the decrease of several pPKC isoforms in the FKBP51-depleted (IR-sensitive) melanoma appeared to us particularly interesting, because PKC is involved in radiation response. Therefore, PKC was chosen for further investigation. After validating by western blot proteomics results, we found that targeting PKC, with the pan PKC inhibitor LY317615 or enzastaurin, significantly enhanced IR-induced cell death. Most interestingly, enzastaurin combined with IR appeared to be effective in eliminating a subset of melanoma cells expressing a stemness marker. Our study highlighted a role for proteomics in finding useful targets to overcome melanoma resistance, and suggested a combination treatment, which deserves to be investigated in a clinical setting.

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Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells

Cited by 116 publications

References 35 publications

Enhancement of oxaliplatin-induced cell apoptosis and tumor suppression by 3-methyladenine in colon cancer

Enhancement of oxaliplatin-induced cell apoptosis and tumor suppression by 3-methyladenine in colon cancer

GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3

A Role for Proteomics in Identifying Targets for Radiosensitizing Strategies in Melanoma: The FKBP51 Paradigm

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