Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer

Koster, Roelof; Pietro, Alessandra di; Timmer‐Bosscha, Hetty; Gibcus, Johan H.; Berg, Anke van den; Suurmeijer, Albert; Bischoff, Rainer; Gietema, Jourik A.; Jong, Steven de

doi:10.1172/jci41939

Cited by 202 publications

(210 citation statements)

References 57 publications

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“…Interestingly, phosphorylated AKT (pAKT) was recently demonstrated to play a role in cisplatin resistance in a preclinical model of GCT through preferential shuttling of p21 to the cytoplasm in which it binds to cyclin-dependent kinase 2, thereby inhibiting the apoptotic response to cisplatin-induced DNA damage (19). Inhibition of pAKT either directly or by blocking PI3K signaling resulted in reversal of cisplatin resistance with a marked increase in apoptosis (19). Thus, although the number of samples with any particular mutation was small, our results support the hypothesis that mutations in these genes could be linked to cisplatin resistance.…”

Section: Discussionmentioning

confidence: 99%

Presence of Somatic Mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in Cisplatin-Resistant Germ Cell Tumors

Feldman

Iyer

Alstine

et al. 2014

Clinical Cancer Research

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Purpose: A previous study noted frequent B-RAF mutations among European patients with cisplatinresistant but not cisplatin-sensitive germ cell tumors (GCT). We sought to validate this finding by assessing for these mutations among patients with GCT at our center.Experimental Design: Adolescent and adult patients with GCT who received cisplatin-based chemotherapy and had tumor tissue available were eligible for participation. Response to cisplatin was reviewed to determine sensitivity and resistance. Tumor DNA was extracted and subjected to Sequenom analysis to detect hotspot alterations in FGFR3, AKT1, PIK3CA, KRAS, HRAS, NRAS, and BRAF with Sanger sequencing for confirmation. Nine GCT cell lines with varying degrees of cisplatin sensitivity and resistance were also assayed by Sequenom.Results: Seventy (24 cisplatin-sensitive; 46 cisplatin-resistant) of 75 patients had tumors with sufficient quality DNA to perform Sequenom. Nineteen mutations were detected among 16 (23%) patients but no BRAF mutations were identified. Similarly, none of the cell lines harbored BRAF mutations. FGFR3 was the most frequent mutation, identified in 13% of both sensitive and resistant samples. All other mutations were exclusive to resistant cases (3 KRAS, 3 AKT1, 3 PIK3CA, and 1 HRAS).Conclusions: BRAF mutations are rare in American patients with GCT, including those with cisplatin resistance. However, other potentially targetable mutations occur in more than 25% of cisplatin-resistant patients. FGFR3, AKT1, and PIK3CA mutations are all reported for the first time in GCT. Whereas FGFR3 mutations occurred with equal frequency in both sensitive and resistant GCTs, mutations in AKT1 and PIK3CA were observed exclusively in cisplatin-resistant tumors.

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Section: Discussionmentioning

confidence: 99%

Presence of Somatic Mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in Cisplatin-Resistant Germ Cell Tumors

Feldman

Iyer

Alstine

et al. 2014

Clinical Cancer Research

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“…Another mechanism involved in CDDP resistance is the downregulation of PTEN by induction of microRNAs (miRNA), such as miR-214 (19) and miR-93 (20) in ovarian cells, or miR-221 in osteosarcoma cells (21). In cisplatin-resistant testicular cancer cells, AKT phosphorylates p21 and induces its cytoplasmic accumulation, protecting cells from cisplatin-induced apoptosis (22). For PDGF factors, an autocrine loop involving PDGF-BB induction in lung cancer stem cells resistant to CDDP (23), in glioma CDDP-resistant cell lines (24), and in tumoral hepatic progenitor cells resistant to CDDP under hypoxia (25) has been described previously.…”

Section: Discussionmentioning

confidence: 99%

The PDGFRβ–AKT Pathway Contributes to CDDP-Acquired Resistance in Testicular Germ Cell Tumors

Juliachs

Muñoz

Moutinho

et al. 2014

Clinical Cancer Research

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Purpose: We examined whether PI3K-AKT or extracellular signal-regulated kinase (ERK) signaling pathways could play a role in the development of cisplatin (CDDP) resistance in testicular germ cell tumor (TGT) cells.Experimental Design: We compared AKT and ERK activation levels in CDDP-sensitive testicular tumor cells and in their corresponding CDDP-resistant-derived cells. We also analyzed these pathways in orthotopic testicular tumors and human patient samples.Results: Our results indicated that there was overactivation of AKT in CDDP-resistant cells compared with sensitive cells, but no effect on activated ERK levels. We observed an increase in mRNA and protein levels for platelet-derived growth factor (PDGF) receptor b and PDGF-B ligand. These were responsible for AKT overactivation in CDDP-resistant cells. When PDGFRb levels were decreased by short hairpin RNA (shRNA) treatment or its activation was blocked by pazopanib, CDDP-resistant cells behaved like sensitive cells. Moreover, CDDP-resistant cells were more sensitive to incubation with PDGFRb inhibitors such as pazopanib or sunitinib than sensitive cells, a finding consistent with these cells being dependent on this signaling pathway. We also found overexpression of PDGFRb and pAKT in CDDP-resistant choriocarcinoma orthotopic tumor versus their CDDP-sensitive counterparts. Finally, we found high PDGFRb levels in human testicular tumors, and overexpression in CDDP-resistant testicular choriocarcinomas compared with the CDDP-sensitive and nontreated tumors.Conclusions: The PDGFRb-AKT pathway plays a critical role in the development of CDDP resistance in testicular tumoral cells. Clin Cancer Res; 20(3); 658-67. Ó2013 AACR.

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“…Phosphorylated p21 that locates in cytoplasm has anti-apoptotic action by inhibiting the apoptotic proteins. Koster et al [49] reported that cytoplasmic p21 conferred resistance against cisplatin-induced apoptosis, while it became pro-apoptotic when it entered in the nucleus by the inhibition of AKT. Involvement in signal transduction of phosphorylated p21 differs depending on the site of the phosphorylated amino acid; Thr145 by AKT [50,51] or…”

Section: Actions Of P21 Depend On Subcellular Localizationmentioning

confidence: 99%

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

Ohkoshi

Yano

Matsuda

2015

WJG

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A well-known tumor suppressor, p21, acts paradoxically by promoting tumor growth in some cellular conditions. These conflicting functions have been demonstrated in association with the HBx gene and in hepatocarcinogenesis. The molecular behavior of p21 depends on its subcellular localization. Nuclear p21 may inhibit cell proliferation and be proapoptotic, while cytoplasmic p21 may have oncogenic and anti-apoptotic functions. Because most typical tumor suppressive proteins also have different effects according to subcellular localization, elucidating the regulatory mechanisms underlying nucleo-cytoplasmic transport of these proteins would be significant and may lead to a new strategy for anti-hepatocellular carcinoma (HCC) therapy. Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor involved in transport of tumor suppressors from nucleus to cytoplasm. Expression of CRM1 is enhanced in a variety of malignancies and in vitro studies have shown the efficacy of specific inhibition of CRM1 against cancer cell lines. Interestingly, interferon may keep p21 in the nucleus; this is one of the mechanisms of its anti-hepatocarcinogenic function. Here we review the oncogenic property of p21, which depends on its subcellular localization, and discuss the rationale underlying a new strategy for HCC treatment and prevention. Core tip: A well-known tumor suppressor, p21, can act paradoxically by promoting tumor growth, depending on its subcellular localization. Nuclear p21 may inhibit cell proliferation while cytoplasmic p21 may be associated with anti-apoptotic and oncogenic functions. REVIEW

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Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer

Cited by 202 publications

References 57 publications

Presence of Somatic Mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in Cisplatin-Resistant Germ Cell Tumors

Presence of Somatic Mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in Cisplatin-Resistant Germ Cell Tumors

The PDGFRβ–AKT Pathway Contributes to CDDP-Acquired Resistance in Testicular Germ Cell Tumors

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

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