| Title |
Inhibition of autophagy exerts anti-colon cancer effects via apoptosis induced by p53 activation and ER stress
|
|---|---|
| Published in |
BMC Cancer, October 2015
|
| DOI | 10.1186/s12885-015-1789-5 |
| Pubmed ID | |
| Authors |
Kosuke Sakitani, Yoshihiro Hirata, Yohko Hikiba, Yoku Hayakawa, Sozaburo Ihara, Hirobumi Suzuki, Nobumi Suzuki, Takako Serizawa, Hiroto Kinoshita, Kei Sakamoto, Hayato Nakagawa, Keisuke Tateishi, Shin Maeda, Tsuneo Ikenoue, Shoji Kawazu, Kazuhiko Koike |
| Abstract |
Although some molecularly targeted drugs for colorectal cancer are used clinically and contribute to a better prognosis, the current median survival of advanced colorectal cancer patients is not sufficient. Autophagy, a basic cell survival mechanism mediated by recycling of cellular amino acids, plays an important role in cancer. Recently, autophagy has been highlighted as a promising new molecular target. The unfolded protein response (UPR) reportedly act in complementary fashion with autophagy in intestinal homeostasis. However, the roles of UPR in colon cancer under autophagic inhibition remain to be elucidated. We aim to clarify the inhibitory effect of autophagy on colon cancer. We crossed K19 (CreERT) and Atg5 (flox/flox) mice to generate Atg5 (flox/flox) /K19 (CreERT) mice. Atg5 (flox/flox) /K19 (CreERT) mice were first treated with azoxymethane/dextran sodium sulfate and then injected with tamoxifen to inhibit autophagy in CK19-positive epithelial cells. To examine the anti-cancer mechanisms of autophagic inhibition, we used colon cancer cell lines harboring different p53 gene statuses, as well as small interfering RNAs (siRNAs) targeting Atg5 and immunoglobulin heavy-chain binding protein (BiP), a chaperone to aid folding of unfolded proteins. Colon tumors in Atg5 (flox/flox) /K19 (CreERT) mice showed loss of autophagic activity and decreased tumor size (the total tumor diameter was 28.1 mm in the control and 20.7 mm in Atg5 (flox/flox) /K19 (CreERT) mice, p = 0.036). We found that p53 and UPR/endoplasmic reticulum (ER) stress-related proteins, such as cleaved caspase 3, and CAAT/enhancer-binding protein homologous protein, are up-regulated in colon tumors of Atg5 (flox/flox) /K19 (CreERT) mice. Although Atg5 and BiP silencing, respectively, increased apoptosis in p53 wild type cells, Atg5 silencing alone did not show the same effect on apoptosis in p53 mutant cells. However, co-transfection of Atg5 and BiP siRNAs led to increased apoptosis in p53 mutant cells. Blocking autophagy has potential in the treatment of colon cancer by inducing apoptosis via p53 and ER stress, and suppressing the UPR pathway is a valid strategy to overcome resistance to autophagic inhibition. |
X Demographics
The data shown below were collected from the profile of 1 X user who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 42 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Netherlands | 1 | 2% |
| Unknown | 41 | 98% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Master | 9 | 21% |
| Researcher | 7 | 17% |
| Student > Ph. D. Student | 7 | 17% |
| Student > Postgraduate | 3 | 7% |
| Student > Bachelor | 3 | 7% |
| Other | 3 | 7% |
| Unknown | 10 | 24% |
| Readers by discipline | Count | As % |
|---|---|---|
| Agricultural and Biological Sciences | 10 | 24% |
| Medicine and Dentistry | 8 | 19% |
| Biochemistry, Genetics and Molecular Biology | 7 | 17% |
| Pharmacology, Toxicology and Pharmaceutical Science | 2 | 5% |
| Chemistry | 2 | 5% |
| Other | 2 | 5% |
| Unknown | 11 | 26% |
Attention Score in Context
This research output has an Altmetric Attention Score of 10. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 27 October 2015.
All research outputs
#3,200,748
of 22,831,537 outputs
Outputs from BMC Cancer
#734
of 8,306 outputs
Outputs of similar age
#47,382
of 283,725 outputs
Outputs of similar age from BMC Cancer
#21
of 225 outputs
Altmetric has tracked 22,831,537 research outputs across all sources so far. Compared to these this one has done well and is in the 85th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 8,306 research outputs from this source. They receive a mean Attention Score of 4.3. This one has done particularly well, scoring higher than 90% of its peers.
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