Slug contributes to gemcitabine resistance through epithelial-mesenchymal transition in CD133+ pancreatic cancer cells

Tsukasa, Koichiro; Ding, Qiang; Yoshimitsu, Makoto; Miyazaki, Yasuhiro; Matsubara, Shigeo; Takao, Sonshin

doi:10.1007/s13577-015-0117-3

Cited by 35 publications

(25 citation statements)

References 37 publications

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“…We have demonstrated the critical roles played by slug in drug resistance in the metastatic ovarian cancer subpopulation. This finding was consistent with several previous reports that slug conferred resistance to anti-cancer drugs 12. , 14.…”

Section: Resultssupporting

confidence: 94%

Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells

Chang

et al. 2019

Acta Pharmaceutica Sinica B

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Metastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment. In this study, SKOV3/T4, a metastatic subpopulation of ovarian cancer SKOV3 cells, was enriched to explore potential interventions against metastatic-associated drug resistance. Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4. Further studies showed that slug activated c-Met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin α V function, which was confirmed by the significant correlation of slug and p-Met levels in 121 ovarian cancer patient samples. Intriguingly, c-Met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both in vitro and in vivo . Additionally, IHC analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients. Taken together, this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-Met in slug-positive ovarian cancer patients with poor prognosis.

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Section: Resultssupporting

confidence: 94%

Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells

Chang

et al. 2019

Acta Pharmaceutica Sinica B

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“…These findings identify a new function for NatD in gene expression regulation, and extend our understanding of epigenetic regulation of EMT via Nt-acetylation of histone H4. Slug, a key regulator of EMT, has been identified as one of the major drivers of chemoresistance, and is associated with cancer stem cell properties 36 , 37 . In our results, we found that Slug is a direct epigenetic target of NatD to mediate EMT processes of lung cancer cells.…”

Section: Discussionmentioning

confidence: 99%

NatD promotes lung cancer progression by preventing histone H4 serine phosphorylation to activate Slug expression

Chen

Deng

et al. 2017

Nat Commun

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N-α-acetyltransferase D (NatD) mediates N-α-terminal acetylation (Nt-acetylation) of histone H4 known to be involved in cell growth. Here we report that NatD promotes the migratory and invasive capabilities of lung cancer cells in vitro and in vivo. Depletion of NatD suppresses the epithelial-to-mesenchymal transition (EMT) of lung cancer cells by directly repressing the expression of transcription factor Slug, a key regulator of EMT. We found that Nt-acetylation of histone H4 antagonizes histone H4 serine 1 phosphorylation (H4S1ph), and that downregulation of Nt-acetylation of histone H4 facilitates CK2α binding to histone H4 in lung cancer cells, resulting in increased H4S1ph and epigenetic reprogramming to suppress Slug transcription to inhibit EMT. Importantly, NatD is commonly upregulated in primary human lung cancer tissues where its expression level correlates with Slug expression, enhanced invasiveness, and poor clinical outcomes. These findings indicate that NatD is a crucial epigenetic modulator of cell invasion during lung cancer progression.

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“…The presence of platelets around breast cancer primary tumour cells was associated with EMT morphological features and chemotherapy resistance [ 106 ]. Independent of platelet activity, EMT has been shown to impart chemotherapy resistance in lung [ 107 ], pancreatic [ 108 ], breast [ 109 ] and ovarian cancers [ 110 ]. Zheng et al, demonstrated using a pancreatic adenocarcinoma mouse model with deleted mesenchymal transcriptional factors, Snail and Twist, that EMT inhibition did not prevent metastasis but contributed significantly to enhanced gemcitabine sensitivity [ 111 ].…”

Section: The Role Of Platelets In Chemotherapy Resistancementioning

confidence: 99%

Targeting Platelets for the Treatment of Cancer

Elaskalani

Berndt

Falasca

et al. 2017

Cancers

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The majority of cancer-associated mortality results from the ability of tumour cells to metastasise leading to multifunctional organ failure and death. Disseminated tumour cells in the blood circulation are faced with major challenges such as rheological shear stresses and cell-mediated cytotoxicity mediated by natural killer cells. Nevertheless, circulating tumour cells with metastatic ability appear equipped to exploit host cells to aid their survival. Despite the long interest in targeting tumour-associated host cells such as platelets for cancer treatment, the clinical benefit of this strategy is still under question. In this review, we provide a summary of the latest mechanistic and clinical evidence to evaluate the validity of targeting platelets in cancer.

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Slug contributes to gemcitabine resistance through epithelial-mesenchymal transition in CD133+ pancreatic cancer cells

Cited by 35 publications

References 37 publications

Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells

Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells

NatD promotes lung cancer progression by preventing histone H4 serine phosphorylation to activate Slug expression

Targeting Platelets for the Treatment of Cancer

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