Examination of survivin expression in 50 chordoma specimens—A histological and in vitro study

Froehlich, Elke Verena; Rinner, Beate; Deutsch, Alexander; Meditz, Katharina; Knausz, Heike; Troppan, Katharina; Scheipl, Susanne; Wibmer, Christine; Leithner, Andreas; Liegl, Bernadette; Lohberger, Birgit

doi:10.1002/jor.22819

Cited by 9 publications

(6 citation statements)

References 29 publications

(32 reference statements)

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“…Survivin is a member of the inhibitor of apoptosis protein family (IAP) and functionally suppresses the terminal effector enzymes caspase-3 and caspase-7 33, 34. Experimental findings have revealed inhibition of Survivin to prevent chordoma cell growth, and as expected, to induce apoptosis 35. Collectively, the decrease in Mcl-1 and Survivin reasonably explains how inhibition of CDK9 may induce apoptosis in chordoma cell lines.…”

Section: Discussionsupporting

confidence: 57%

Aberrant CDK9 expression within chordoma tissues and the therapeutic potential of a selective CDK9 inhibitor LDC000067

Shen¹,

Dean²,

Yu³

et al. 2020

J. Cancer

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Objectives: Chordomas are slow-growing malignancies that commonly affect vital neurological structures. These neoplasms are highly resistant to current chemotherapeutic regimens and often recur after surgical intervention. Therefore, there is an urgent need to identify molecular targets and more robust drugs to improve chordoma patient outcomes. It is well accepted that cyclin-dependent protein kinase 9 (CDK9) has tumorigenic roles in various cancers; however, the expression and significance of CDK9 in chordoma remains unknown. Methods: Expression of CDK9 in chordoma cell lines and tumor tissues was examined by Western blot and immunohistochemistry (IHC). The correlation between CDK9 expression in patient tissues and clinical prognosis was analyzed. The functional roles of CDK9 in chordoma were investigated after the addition of small interfering RNA (siRNA) and CDK9 inhibitor (LDC000067). Cell growth and proliferation were assessed with MTT and clonogenic assays. The effect of CDK9 inhibition on chordoma cells was further evaluated with a three-dimensional (3D) cell culture model which mimics the in vivo environment. Results: CDK9 was expressed in both chordoma cell lines and chordoma tissues. High-expression of CDK9 correlated with recurrence and poor outcomes for chordoma patients. CDK9 silencing with siRNA decreased growth and proliferation of chordoma cells and lowered levels of Mcl-1 and RNA polymerase II (RNAP II) phosphorylation. Pharmacological inhibition of CDK9 with the small molecular inhibitor LDC000067 reduced cell growth, supported apoptosis, suppressed cell colony formation in a clonogenic assay, and decreased spheroid growth in 3D culture. Conclusion: We demonstrate that CDK9 expression in chordoma correlates with patient outcome, and, when inhibited, chordoma cell growth and proliferation significantly decreases. Taken together, these results support CDK9 as an emerging potential target in chordoma therapy.

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Section: Discussionsupporting

confidence: 57%

Aberrant CDK9 expression within chordoma tissues and the therapeutic potential of a selective CDK9 inhibitor LDC000067

Shen¹,

Dean²,

Yu³

et al. 2020

J. Cancer

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“…Froehlich et al then explored the function of survivin in chordoma cells [ 79 ] and evaluated survivin expression in 50 chordoma cases (34 primary and 16 recurrent) from 44 patients using IHC. Twenty-three of 34 (68%) primary chordoma cases and 16 of 16 recurrent chordomas stained positive.…”

Section: Potential Future Treatmentsmentioning

confidence: 99%

“…The treatment reduced survivin protein expression and increased markers of apoptosis. Based on their findings, the authors suggested that YM155, which has been demonstrated to be safe in other diseases [ 80 – 82 ], could be a potential therapeutic agent for use in chordoma [ 79 ].…”

Section: Potential Future Treatmentsmentioning

confidence: 99%

Chordoma: The Quest for Better Treatment Options

Heery

2016

Oncol Ther

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Chordoma is an extremely rare cancer, with an incidence of about one case per million persons per year in the USA and Europe (about 300 and 450 cases per year, respectively). The estimated median overall survival of patients with chordoma is approximately 6–7 years, yielding a rough estimate of chordoma prevalence at about 2000 in the USA and 3000 in Europe. Primary tumor develops along the axial spine between the clivus and sacrum and develops from the residual embryonic notochord. Brachyury (T), a transcription factor required for normal embryonic development, is expressed in the notochord and overexpressed in almost all cases of chordoma. The primary treatment for chordoma is surgical excision with wide local margins, when possible. Radiotherapy also plays a significant role in the adjuvant setting and when surgery is not possible. Unfortunately, in the advanced and/or metastatic setting, where the role of surgery and/or radiation is less clear, treatment options are very limited. To date, there have been no randomized, controlled trials in chordoma that have resulted in defined agents of clinical benefit for systemic treatment. This review briefly describes the natural history and initial treatment of chordoma and focuses on treatment options for advanced disease and potential avenues of research that may lead to improved treatment options in the future.

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“…Survivin belongs to the inhibitor of apoptosis (IAP) gene family and has an anti-apoptotic effect when it directly binds to caspase-3, a critical effector of apoptosis, which inhibits caspase-3 activation (33). It is important to note that survivin is also expressed in chordoma patient specimens and that the inhibition of survivin prevented chordoma cell growth (34). Moreover, the knockdown of survivin by RNAi reduced the clonogenic survival of human sarcoma cells (35).…”

Section: Discussionmentioning

confidence: 99%

Expression and Therapeutic Potential of SOX9 in Chordoma

Chen

Garbutt

Spentzos

et al. 2017

Clinical Cancer Research

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Purpose Conventional chemotherapeutic agents are ineffective in the treatment of chordoma. We investigated the functional roles and therapeutic relevance of the sex-determining region Y (SRY)-box 9 (SOX9) in chordoma. Experimental Design SOX9 expression was examined by immunohistochemistry (IHC) using 50 chordoma tissue samples. SOX9 expression in chordoma cell lines was examined by Western blot and immunofluorescence assays. We used synthetic human SOX9 siRNA to inhibit the expression of SOX9. Cell proliferation ability and cytotoxicity of inhibiting SOX9 were assessed by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) and clonogenic assays. The effect of SOX9 knockdown on chordoma cell motility was evaluated by a wound healing assay and a transwell invasion chamber assay. Knockdown of SOX9 induced apoptosis, cell cycle arrest as well as decreased expression of cancer stem cell markers were determined by Western blot and flow cytometric assays. The effect of the combination of SOX9 siRNA and the chemotherapeutic drug doxorubicin/cisplatin on chordoma cells was assessed by a MTT assay. Results Tissue microarray (TMA) and IHC analysis showed that SOX9 is broadly expressed in chordomas and that higher expression levels of SOX9 correlated with a poor prognosis. RNA interference (RNAi)-mediated knockdown of SOX9 inhibited chordoma cell growth, decreased cell motility, and induced apoptosis as well as cell cycle arrest. Moreover, the combination of SOX9 inhibition and chemotherapeutic drugs had an enhanced anti-cancer effect on chordoma cells. Conclusions Our results demonstrate that SOX9 plays a crucial role in chordoma. Targeting SOX9 provides a new rationale for treatment of chordoma.

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Examination of survivin expression in 50 chordoma specimens—A histological and in vitro study

Cited by 9 publications

References 29 publications

Aberrant CDK9 expression within chordoma tissues and the therapeutic potential of a selective CDK9 inhibitor LDC000067

Aberrant CDK9 expression within chordoma tissues and the therapeutic potential of a selective CDK9 inhibitor LDC000067

Chordoma: The Quest for Better Treatment Options

Expression and Therapeutic Potential of SOX9 in Chordoma

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