Inhibition of <i>TWIST1</i> Leads to Activation of Oncogene-Induced Senescence in Oncogene-Driven Non–Small Cell Lung Cancer

Burns, Timothy F.; Dobromilskaya, Irina; Murphy, Sara C.; Gajula, Rajendra P.; Thiyagarajan, Saravanan; Chatley, Sarah N.; Aziz, Khaled; Cho, Yoon Jae; Tran, Phuoc T.; Rudin, Charles M.

doi:10.1158/1541-7786.mcr-12-0456

Cited by 55 publications

(90 citation statements)

References 47 publications

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“…Cell senescence plays an important role in cancer development and progression [48], and therapy-induced senescence (TIS) has emerged as a novel therapeutic approach for cancer eradication [42, 49, 50]. Several TIS pathways have been identified that induce cell senescence and the eradication of established tumors, such as inactivation of MYC, SKP2, or CK2 [51, 52].…”

Section: Discussionmentioning

confidence: 99%

SIRT1 Inactivation Evokes Antitumor Activities in NSCLC through the Tumor Suppressor p27

Zhu

Chiao

Enzer

et al. 2015

Molecular Cancer Research

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P27Kip1 (CDKN1B) regulates cellular proliferation and senescence, and p27Kip1 deficiency in cancer is strongly correlated with poor prognosis of multiple cancer types. Understanding the mechanism of p27Kip1 loss in cancer and the consequences of restoring p27Kip1 levels is therefore critical for effective management during therapy. Here, SIRT1, a class III histone deacetylase (HDAC), is identified as an important regulator of p27Kip1 expression. Mechanistically, SIRT1 reduces p27Kip1 expression by decreasing p27Kip1 protein stability through the ubiquitin-proteasome pathway. In addition, SIRT1 silencing suppresses NSCLC proliferation and induces senescence in a p27Kip1-dependent manner. Furthermore, SIRT1 silencing dramatically suppresses tumor formation and proliferation in two distinct NSCLC xenograft mouse models. Collectively, these data not only demonstrate that SIRT1 is an important regulator of p27Kip1 but that SIRT inhibition induces senescence and anti-growth potential in lung cancer in vivo. Implications SIRT1 is a key regulator of p27 protein levels and SIRT1 inhibition is a viable strategy for NSCLC therapy by means of p27 reactivation.

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Section: Discussionmentioning

confidence: 99%

SIRT1 Inactivation Evokes Antitumor Activities in NSCLC through the Tumor Suppressor p27

Zhu

Chiao

Enzer

et al. 2015

Molecular Cancer Research

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“…Thus, RC-6 induced some cells to give rise to cellular senescence. Previous studies indicated that p16, p21 and p27 are related to cellular senescence in senescence cells (49)(50)(51)(52)(53). Therefore, these proteins were determined in the present study.…”

Section: Senescence Characteristics In Nt2 Cells After Rc-6 Treatmentmentioning

confidence: 89%

“…Previous studies indicated that β-galactosidase activity is a major characteristic found in senescence cells and is generally applied to senescence detection (65)(66)(67). In addition, many studies have reported that p16 and p21 protein levels are increased in senescence cells (50)(51)(52)(53). At present, a small fraction of RC-6-treated NT2 cells can express β-galactosidase activity.…”

Section: Discussionmentioning

confidence: 99%

RC-6 ribonuclease induces caspase activation, cellular senescence and neuron-like morphology in NT2 embryonal carcinoma cells

et al. 2014

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Abstract.Frog ribonucleases have been demonstrated to have anticancer activities. However, whether RC-6 ribonuclease exerts anticancer activity on human embryonal carcinoma cells remains unclear. In the present study, RC-6 induced cytotoxicity in NT2 cells (a human embryonal carcinoma cell line) and our studies showed that RC-6 can exert anticancer effects and induce caspase-9 and -3 activities. Moreover, to date, there is no evidence that frog ribonuclease-induced cytotoxicity effects are related to cellular senescence. Therefore, our studies showed that RC-6 can increase p16 and p21 protein levels and induce cellular senescence in NT2 cells. Notably, similar to retinoic acid-differentiated NT2 cells, neuron-like morphology was found on some remaining live cells after RC-6 treatment. In conclusion, our study is the first to demonstrate that RC-6 can induce cytotoxic effects, caspase-9/-3 activities, cellular senescence and neuron-like morphology in NT2 cells.

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“…Emerging evidences have indicated that Twist1 played a crucial role in cancer initiation and progression through its ability to inhibit DNA damage-induced apoptosis and induction of the epithelial-mesenchymal transition (EMT) [13][14][15][16]. Suppression of Twist1 resulted in significant growth inhibition of multiple defined oncogenic drives-induced NSCLC [17]. In addition, silencing of Twist1 sensitized NSCLC cells to cisplatin via stimulating AMPK-induced mTOR/S6K1 inhibition which led to a decrease of Mcl-1 protein [18].…”

Section: Introductionmentioning

confidence: 99%

TPPP3 Promotes Cell Proliferation, Invasion and Tumor Metastasis via STAT3/ Twist1 Pathway in Non-Small-Cell Lung Carcinoma

Li¹,

Bai²,

Xu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Non-small-cell lung carcinoma (NSCLC) is the leading cause of cancer death, with tumor metastasis being mainly responsible for lung cancer-associated mortality. Our previous studies have found that tubulin polymerization promoting protein family member 3 (TPPP3) acted as a potential oncogene in NSCLC. Little is known about the function of TPPP3 in tumor metastasis. Methods: RT-qPCR and IHC were used to investigate the expression of TPPP3 in NSCLC tissues. CCK8 assay and transwell assay were used to measure proliferation and migration of NSCLC cells in vitro and xenograft model was performed to assess the tumor growth and metastasis in vivo. Results: In the present study, upregulation of TPPP3 was found to correlate with an increased metastasis capability of NSCLC. Ectopic expression of TPPP3 significantly enhanced cell proliferation in vitro and promoted tumor growth in vivo. Furthermore, overexpression of TPPP3 remarkably promoted NSCLC cell migration and invasion along with the upregulation of Twist1 both in vitro and in vivo. Further investigations showed that activation of STAT3 was required for TPPP3-mediated upregulation of Twist1, cell migration and invasion. A strong positive correlation between TPPP3 and Twist1 expression was identified in NSCLC tissues. Patients with low TPPP3 or low Twist1 in NSCLC tissues had a better prognosis with longer overall survival (OS) and disease-free survival (DFS). Conclusion: Overall, this study demonstrates that TPPP3 promotes the metastasis of NSCLC through the STAT3/Twist1 pathway.

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Inhibition of TWIST1 Leads to Activation of Oncogene-Induced Senescence in Oncogene-Driven Non–Small Cell Lung Cancer

Cited by 55 publications

References 47 publications

SIRT1 Inactivation Evokes Antitumor Activities in NSCLC through the Tumor Suppressor p27

SIRT1 Inactivation Evokes Antitumor Activities in NSCLC through the Tumor Suppressor p27

RC-6 ribonuclease induces caspase activation, cellular senescence and neuron-like morphology in NT2 embryonal carcinoma cells

TPPP3 Promotes Cell Proliferation, Invasion and Tumor Metastasis via STAT3/ Twist1 Pathway in Non-Small-Cell Lung Carcinoma

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