Analysis of apoptosome dysregulation in pancreatic cancer and of its role in chemoresistance

Corvaro, Marco; Fuoco, Claudia; Wagner, Martin; Cecconi, Francesco

doi:10.4161/cbt.6.2.3622

Cited by 9 publications

(11 citation statements)

References 32 publications

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“…The mechanism of Apaf-1 entry into the nucleus [55] is not known to date. Since there is some evidence that UACA is responsible for the intranuclear Apaf-1 protein trans-location [56], we therefore tested the level of UACA mRNA expression under the same conditions as described above. Interestingly, the expression level of this transcript was significantly lower only in NCI-H460 cells (Figure 6C and F).…”

Section: Resultsmentioning

confidence: 99%

Minnelide: A Novel Therapeutic That Promotes Apoptosis in Non-Small Cell Lung Carcinoma In Vivo

et al. 2013

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BackgroundMinnelide, a pro-drug of triptolide, has recently emerged as a potent anticancer agent. The precise mechanisms of its cytotoxic effects remain unclear.MethodsCell viability was studied using CCK8 assay. Cell proliferation was measured real-time on cultured cells using Electric Cell Substrate Impedence Sensing (ECIS). Apoptosis was assayed by Caspase activity on cultured lung cancer cells and TUNEL staining on tissue sections. Expression of pro-survival and anti-apoptotic genes (HSP70, BIRC5, BIRC4, BIRC2, UACA, APAF-1) was estimated by qRTPCR. Effect of Minnelide on proliferative cells in the tissue was estimated by Ki-67 staining of animal tissue sections.ResultsIn this study, we investigated in vitro and in vivo antitumor effects of triptolide/Minnelide in non-small cell lung carcinoma (NSCLC). Triptolide/Minnelide exhibited anti-proliferative effects and induced apoptosis in NSCLC cell lines and NSCLC mouse models. Triptolide/Minnelide significantly down-regulated the expression of pro-survival and anti-apoptotic genes (HSP70, BIRC5, BIRC4, BIRC2, UACA) and up-regulated pro-apoptotic APAF-1 gene, in part, via attenuating the NF-κB signaling activity.ConclusionIn conclusion, our results provide supporting mechanistic evidence for Minnelide as a potential in NSCLC.

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Section: Resultsmentioning

confidence: 99%

Minnelide: A Novel Therapeutic That Promotes Apoptosis in Non-Small Cell Lung Carcinoma In Vivo

et al. 2013

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“…We discovered a primary pancreatic cancer-and-metastasis-specific intronic integration event located between two APAF1 exons (apoptotic peptidase activating factor 1) 700 bp downstream and 1 kb upstream, respectively. APAF1 is a component of the apoptosome that is dysregulated in pancreatic ductal adenocarcinomas (Corvaro et al 2007). In another pancreatic cancer patient, an intronic L1 in the GDNF gene was also present in both the primary cancer and its metastasis.…”

Section: Insertions In Known or Candidate Cancer Driver Genesmentioning

confidence: 99%

Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution

et al. 2015

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Somatic L1 retrotransposition events have been shown to occur in epithelial cancers. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds, and many were present in multiple tumor sections, implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth.

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“…Multiple types of cancer harbor apoptosome dysfunction causing inhibition of cancer cell apoptosis and may be associated with the development of resistance during cancer therapy (Corvaro et al, 2007; Fadeel et al, 2008; Hajra and Liu, 2004; Ledgerwood and Morison, 2009; Liu et al, 2002; Schafer and Kornbluth, 2006; Yang et al, 2003). In this direction, multiple small molecules targeting apoptosome have been discovered, which may restore apoptosome function and enhance apoptotic cell death in cancer (Qi et al, 2010; Rodina et al, 2007; Tan et al, 2011; Yang et al, 2003).…”

Section: Endogenous Prosurvival Factorsmentioning

confidence: 99%

Mitochondrial and postmitochondrial survival signaling in cancer

Yadav

Chandra

2014

Mitochondrion

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Cancer cells are resistant to conventional chemotherapy and radiotherapy, however, the molecular mechanisms of resistance to therapy remain unclear. Cellular survival machinery protects mitochondrial integrity against endogenous or exogenous stresses. Prodeath molecules orchestrate around mitochondria to initiate and execute cell death in cancer, and also play an under appreciated role in survival of cancer cells. Prosurvival mechanisms can operate at mitochondrial and postmitochondrial levels to attenuate core apoptotic death program. It is intriguing to explore how prosurvival and prodeath molecules crosstalk to regulate mitochondrial functions leading to increased cancer cell survival. This review describes some putative survival mechanisms at mitochondria, which may play significant role in designing effective agents for cancer prevention and therapy. These survival pathways may also have significance in understanding other human pathophysiological conditions including diabetes, cardiovascular, autoimmune, and neurodegenerative diseases.

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Analysis of apoptosome dysregulation in pancreatic cancer and of its role in chemoresistance

Cited by 9 publications

References 32 publications

Minnelide: A Novel Therapeutic That Promotes Apoptosis in Non-Small Cell Lung Carcinoma In Vivo

Minnelide: A Novel Therapeutic That Promotes Apoptosis in Non-Small Cell Lung Carcinoma In Vivo

Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution

Mitochondrial and postmitochondrial survival signaling in cancer

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