Apoptosis Suppression by Somatic Cell Transfer of Bcl-2 Promotes Sonic Hedgehog–Dependent Medulloblastoma Formation in Mice

McCall, Todd D.; Pedone, Carolyn A.; Fults, Daniel W.

doi:10.1158/0008-5472.can-06-4177

Cited by 47 publications

(40 citation statements)

References 25 publications

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“…These observations imply that MYCN is necessary but not sufficient to drive MB in the mouse, a result aligned with that of Fults and coworkers (Browd et al 2006), who modeled MB by injecting retroviruses into a small field of cerebellar progenitor cells in vivo and established that N-myc could cooperate with Shh in driving MB. However, N-myc could not by itself drive tumor formation (Browd et al 2006); and no tumors were generated even when ectopically expressing a mutationally stabilized form of N-myc, alone or in combination with the anti-apoptotic protein Bcl-2 (Browd et al 2006;McCall et al 2007). Similarly, in our experiments, misexpression of a MYCN transgene in a larger field of cells led to MB tumors only through acquisition of secondary genetic abnormalities.…”

Section: Discussionmentioning

confidence: 45%

“…Experiments in genetically engineered mice demonstrate that N-myc is required for MB development (Hatton et al 2006), suggesting that human tumors could also arise, in part, through misexpression of MYCN (Kenney et al 2003;Oliver et al 2003;Hatton et al 2006;Kessler et al 2009;Thomas et al 2009). To date, however, N-myc overexpression (alone or in combination with Gli1, IGF-II, or Bcl-2) has failed to initiate MB in any experimental model (Browd et al 2006;McCall et al 2007).…”

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confidence: 99%

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Pleiotropic role forMYCNin medulloblastoma

Swartling¹,

Grimmer²,

Hackett³

et al. 2010

Genes Dev.

150

191

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Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Sonic Hedgehog (SHH) signaling drives a minority of MB, correlating with desmoplastic pathology and favorable outcome. The majority, however, arises independently of SHH and displays classic or large cell anaplastic (LCA) pathology and poor prognosis. To identify common signaling abnormalities, we profiled mRNA, demonstrating misexpression of MYCN in the majority of human MB and negligible expression in normal cerebella. We clarified a role in pathogenesis by targeting MYCN (and luciferase) to cerebella of transgenic mice. MYCN-driven MB showed either classic or LCA pathologies, with Shh signaling activated in~5% of tumors, demonstrating that MYCN can drive MB independently of Shh. MB arose at high penetrance, consistent with a role for MYCN in initiation. Tumor burden correlated with bioluminescence, with rare metastatic spread to the leptomeninges, suggesting roles for MYCN in both progression and metastasis. Transient pharmacological down-regulation of MYCN led to both clearance and senescence of tumor cells, and improved survival. Targeted expression of MYCN thus contributes to initiation, progression, and maintenance of MB, suggesting a central role for MYCN in pathogenesis.

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Section: Discussionmentioning

confidence: 45%

mentioning

confidence: 99%

Pleiotropic role forMYCNin medulloblastoma

Swartling¹,

Grimmer²,

Hackett³

et al. 2010

Genes Dev.

150

191

View full text Add to dashboard Cite

show abstract

“…Other antiapoptotic signals, such as miR-21, have been shown to be universally upregulated across all medulloblastoma subgroups (4). The overexpression of antiapoptotic proteins has recently been shown to be critical to the development of medulloblastomas in a mouse model (14) and the efficacy of radiotherapy has been shown to depend on activation of the apoptotic pathway (15). In medulloblastoma samples, high levels of antiapoptotic proteins have been shown to correlate with tumor grade and poor outcomes (16,17).…”

Section: Introductionmentioning

confidence: 99%

Targeting the Inhibitor of Apoptosis Proteins as a Novel Therapeutic Strategy in Medulloblastoma

Keating

Tsoli

Hallahan

et al. 2012

Molecular Cancer Therapeutics

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Medulloblastoma is the most common malignant brain tumor of childhood. Novel therapeutic strategies are urgently needed to overcome cytotoxic resistance. We hypothesized that antiapoptotic signals contribute to resistance and that treatment with proapoptotic agents could increase the efficacy of conventional therapies. A PCR array was used to assess the status of the apoptotic signaling pathway in medulloblastoma cells after treatment with cytotoxic chemotherapy. Treatment with cisplatin led to the upregulation of antiapoptotic signals, including inhibitor of apoptosis proteins (IAP), in medulloblastoma cells. We subsequently investigated the synergistic effect of a small-molecule IAP inhibitor, LBW242, in combination with cisplatin and/or radiotherapy in three human medulloblastoma cell lines and 5 short term primary patient medulloblastoma cultures. The addition of LBW242 to chemotherapy resulted in significantly increased antitumor activity with a similar effect observed in combination with radiotherapy. Measurement of caspase-8 and -9 activity indicated that the synergy resulted from induction of both the intrinsic and extrinsic apoptotic pathways. Apoptosis was confirmed by Annexin V staining and activation of caspases 3/7. Xenograft models were used to evaluate the mechanism of action and efficacy in vivo. The combination therapy significantly reduced the tumor burden in a medulloblastoma xenograft model and TUNEL analysis in a medulloblastoma orthograft confirmed in vivo induction of apoptosis. These findings support the strategy of targeting IAPs in combination with cytotoxic therapy as a novel treatment strategy for patients with medulloblastoma.

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“…Warncke et al, 1997). Ketamine can be used as a preemptive analgesic (Wong et al, 1997;McCall et al, 2007) for cancer-related pain (Roytblat et al, 1993;Clark and Kalan, 1995;Mercadante et al, 2000) or the diffuse pain of fibromyalgia (Sorensen et al, 1995). Any chemical may have more than one kind of function.…”

Section: Discussionmentioning

confidence: 99%

Ketamine used as an acesodyne in human breast cancer therapy causes an undesirable side effect, upregulating anti-apoptosis protein Bcl-2 expression

J²,

Xie³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Ketamine is a dissociative anesthetic agent that has been widely used in surgery and for relieving pain in chronic cancer patients. We applied ketamine to breast cancer cell line MDA-MB-231 to detect the effect of treatment and molecular mechanisms involved. We found that ketamine can upregulate the level of anti-apoptosis protein Bcl-2, which promotes breast cancer cell invasion and proliferation. Knockdown of Bcl-2 could inhibit the increase of Bcl-2 and reduce the invasion and proliferation caused by ketamine in human breast cancer cells. Our findings provide new insight into the effects of ketamine in cancer treatment; we suggest that ketamine, which has been widely used in cancer operations and for relieving pain in chronic cancer patients, may be not the best choice because it can worsen the cancer through promotion of anti-apoptosis.

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Apoptosis Suppression by Somatic Cell Transfer of Bcl-2 Promotes Sonic Hedgehog–Dependent Medulloblastoma Formation in Mice

Abstract: Medulloblastomas are malignant brain tumors that arise in the cerebellum in children.

Cited by 47 publications

References 25 publications

Pleiotropic role forMYCNin medulloblastoma

Pleiotropic role forMYCNin medulloblastoma

Targeting the Inhibitor of Apoptosis Proteins as a Novel Therapeutic Strategy in Medulloblastoma

Ketamine used as an acesodyne in human breast cancer therapy causes an undesirable side effect, upregulating anti-apoptosis protein Bcl-2 expression

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