Chronic mTOR activation promotes cell survival in Merkel cell carcinoma

Lin, Zhenyu; McDermott, Amelia; Shao, Longquan; Kannan, Aarthi; Morgan, Michael B.; Stack, Brendan C.; Moreno, Mauricio A.; Davis, Donald R.; Cornelius, Lynn A.; Gao, Ling

doi:10.1016/j.canlet.2013.11.005

Cited by 43 publications

(47 citation statements)

References 49 publications

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“…20 MKL-1 and MKL-2 cell lines are gifts from DR Becker (University of Graz, Austria). All the MCC cells were cultured with RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) and 10% penicillinstreptomycin-L-glutamine and incubated at 37 C in a humidified incubator with 5% CO2.…”

Section: Methodsmentioning

confidence: 99%

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Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma

et al. 2015

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Section: Methodsmentioning

confidence: 99%

“…MCC-3 and MCC-5 were established in our laboratory. 20 MKL-1 and MKL-2 were a gift from Dr. Becker (University of Graz, Austria). 21 All four MCC cell lines grew in suspension in culture and expressed characteristic markers of MCC as described previously.…”

Section: Introductionmentioning

confidence: 99%

Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma

et al. 2015

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“…In accordance with institutional approvals for human study protocol, we have established three primary human Merkel cell carcinoma cell lines (MCC-2, MCC-3 and MCC-5) derived from lymph node metastases of three MCC patients as previously described (36, 37). Primary MCC cells were cultured with RPMI-1640 medium containing 10% fetal bovine serum (FBS) and 10% penicillin-streptomycin-L-glutamine and incubated at 37 °C in a humidified incubator with 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…PCR was performed with 120ng of genomic DNA using the Taq DNA polymerase (Invitrogen) in a final volume of 50 l for 30–35 cycles. Primer sets for LT3 and MCPVS1 were used as published previously (36). …”

Section: Methodsmentioning

confidence: 99%

BET Protein Inhibitor JQ1 Attenuates Myc-Amplified MCC Tumor Growth In Vivo

Shao

Kannan

Lin³

et al. 2014

Cancer Research

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Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin currently with no cure. In this study, we have first demonstrated that c-Myc overexpression is common in MCC. By targeting c-Myc, bromodomain inhibitors have demonstrated antitumor efficacy in several preclinical human cancer models. Thus we interrogated the role of c-Myc inhibition in MCC with c-Myc amplification by employing the BET inhibitor JQ1. We have uncovered that c-Myc can be regulated by JQ1 in MCC cells with pathological c-Myc activation. Moreover, JQ1 potently abrogates c-Myc expression in MCC cells and causes marked G1 cell cycle arrest. Mechanistically, JQ1 induced cell cycle arrest coincides with downrgulation of cyclin D1 and upregulation of p21, p27 and p57, whereas JQ1 exerts no effect on apoptosis in MCC cells. Further knockdown of p21, p27 or p57 by shRNA partially protects cells from JQ1 induced cell cycle arrest. Additionally, c-Myc knockdown by shRNA generates significant cell cycle arrest, suggesting that c-Myc overexpression plays a role in MCC pathogenesis. Most importantly, JQ1 significantly attenuates tumor growth in xenograft MCC mouse models. Our results provide initial evidence indicating the potential clinical utility of BET protein inhibitors in the treatment of MCC with pathologic activation of c-Myc.

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“…Previously, Akt hyperphosphorylation has been found in MCV-independent MCC (7,8). In addition, chronic mTOR activation has been found to promote cell survival in MCC (9). Therefore, the PI3K/Akt/mTOR pathway is a promising target for the management of MCC.…”

Section: Introductionmentioning

confidence: 98%

Effect of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against human Merkel cell carcinoma MKL-1 cells

et al. 2015

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Abstract. Merkel cell carcinoma (MCC) is an aggressive skin cancer with an increasing incidence. Aberrant activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in human cancers and has been revealed to play an important function in cell proliferation, metabolism and tumorigenesis. In the present study, NVP-BEZ235, a dual PI3K/mTOR inhibitor, was revealed to be effective in inhibiting proliferation and inducing cell cycle arrest in MKL-1 cells. Additional investigations revealed that NVP-BEZ235 attenuated PI3K/Akt/mTOR signaling and upregulated the levels of the cell cycle inhibitors p21 and p27. Overall, the present results possess considerable implications for future development of dual PI3K/mTOR inhibitor as potential agents in the management of MCC.

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Chronic mTOR activation promotes cell survival in Merkel cell carcinoma

Cited by 43 publications

References 49 publications

Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma

Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma

BET Protein Inhibitor JQ1 Attenuates Myc-Amplified MCC Tumor Growth In Vivo

Effect of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against human Merkel cell carcinoma MKL-1 cells

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