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Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice.

ABSTRACT: Cancer cells often acquire capabilities to evade cell death induced by current chemotherapeutic treatment approaches. Caspase-8, a central initiator of death receptor-mediated apoptosis, for example, is frequently inactivated in human cancers via multiple mechanisms such as mutation. Here, we show an approach to overcome cell death resistance in caspase-8-deficient colorectal cancer (CRC) by induction of necroptosis. In both a hereditary and a xenograft mouse model of caspase-8-deficient CRC, second mitochondria-derived activator of caspase (SMAC) mimetic treatment induced massive cell death and led to regression of tumors. We further demonstrate that receptor-interacting protein kinase 3 (RIP3), which is highly expressed in mouse models of CRC and in a subset of human CRC cell lines, is the deciding factor of cancer cell susceptibility to SMAC mimetic-induced necroptosis. Thus, our data implicate that it may be worthwhile to selectively evaluate the efficacy of SMAC mimetic treatment in CRC patients with caspase-8 deficiency in clinical trials for the development of more effective personalized therapy.

SUBMITTER: He GW

PROVIDER: S-EPMC5460989 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice.

He Gui-Wei GW Günther Claudia C Thonn Veronika V Yu Yu-Qiang YQ Martini Eva E Buchen Barbara B Neurath Markus F MF Stürzl Michael M Becker Christoph C

The Journal of experimental medicine 20170505 6

Cancer cells often acquire capabilities to evade cell death induced by current chemotherapeutic treatment approaches. Caspase-8, a central initiator of death receptor-mediated apoptosis, for example, is frequently inactivated in human cancers via multiple mechanisms such as mutation. Here, we show an approach to overcome cell death resistance in <i>caspase-8</i>-deficient colorectal cancer (CRC) by induction of necroptosis. In both a hereditary and a xenograft mouse model of <i>caspase-8</i>-def ...[more]

PMID: 28476895

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Project description:Breast cancer is the most common cancer in women. The human epidermal growth factor receptor 2 (HER2) overexpressing subtype is related to poor prognosis with an aggressive phenotype and is reported as one of the most commonly seen subtypes. Trastuzumab is prevalently used as a treatment method for HER2+ breast cancer however, resistance to the drug frequently occurs following the treatment. MicroRNAs (miRNAs) are 19-23 nucleotide long small RNAs, which regulate gene expression at post-transcriptional level and studies show that there are differentially expressed miRNAs between drug sensitive and resistant groups, indicating that they might have some key roles in drug effectiveness. In this study, the aim is to find out the role of miR-216b-5p in trastuzumab resistance. SK-BR-3 cells developed resistance to trastuzumab after continuous treatment with increasing concentrations of the drug for 6 months. To investigate the effect of miR-216b-5p on cancer cell behavior in resistance state, proliferation, motility, and invasion capacities of these resistant cells were analyzed by xCELLigence real-time cell analyzer. To further understand the molecular mechanisms underlying the regulation of resistant SK-BR-3 cells by miR-216b-5p, microarray analysis was performed. Apoptosis analysis was also performed since the pathway enrichment analysis pointed out cell death related pathways. The proliferation, motility, and invasion capacities of the miR-216b-5p transfected resistant cells were diminished compared to sensitive cells. We identified the necroptosis signaling pathway as the result of microarray and pathway enrichment analyses. STAT1, IRF9, and PKR were validated as the significant elements of the pathway, which are also the putative targets of miR-216b-5p. Our apoptosis analysis showed that a significant amount of trastuzumab resistant SK-BR-3 cells entered to late apoptosis/necrosis stage upon miR-216b-5p overexpression, it could be concluded that reexpression of miR-216b-5p sensitizes trastuzumab resistance through necroptosis in breast cancer.

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Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice.

Publications

Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice.

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