Limits...
Dormancy of cancer cells with suppression of AKT activity contributes to survival in chronic hypoxia.

Endo H, Okuyama H, Ohue M, Inoue M - PLoS ONE (2014)

Bottom Line: ATP turnover, an indicator of energy demand, was markedly decreased and accompanied by reduced AKT phosphorylation.Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro and a decreased number of dormant cells in vivo.Primary colorectal cancer cells in dormancy were resistant to chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.

ABSTRACT
A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to recent progress in understanding the acute response of cancer cells to hypoxia, the characteristics of tumor cells in chronic hypoxia remain elusive. We have identified a pancreatic cancer cell line, AsPC-1, that is exceptionally able to survive for weeks under 1% oxygen conditions while most tested cancer cell lines die after only some days under these conditions. In chronic hypoxia, AsPC-1 cells entered a state of dormancy characterized by no proliferation, no death, and metabolic suppression. They reversibly switched to active status after being placed again in optimal culture conditions. ATP turnover, an indicator of energy demand, was markedly decreased and accompanied by reduced AKT phosphorylation. Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro and a decreased number of dormant cells in vivo. In contrast to most cancer cell lines, primary-cultured colorectal cancer cells easily entered the dormant status with AKT suppression under hypoxia combined with growth factor-depleted conditions. Primary colorectal cancer cells in dormancy were resistant to chemotherapy. Thus, the ability to survive in a deteriorated microenvironment by entering into dormancy under chronic hypoxia might be a common property among cancer cells. Targeting the regulatory mechanism inducing this dormant status could provide a new strategy for treating cancer.

Show MeSH

Related in: MedlinePlus

Primary colorectal cancer in dormant status is resistant to chemotherapy.A) CTOS samples were cultured in medium with (GF+) or without (GF−) growth factors, and under 20% O2 or 1% O2 conditions. 5FU or SN38 were added to medium and treated for 7 days (indicated by black bars). At day 7, medium was changed to fresh StemPro hESC containing growth factors (black arrows), and CTOS samples were allowed to regrow under 20% O2. B) Representative images of CTOS samples in (A). Scale bar  =  100 µm.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4048292&req=5

pone-0098858-g006: Primary colorectal cancer in dormant status is resistant to chemotherapy.A) CTOS samples were cultured in medium with (GF+) or without (GF−) growth factors, and under 20% O2 or 1% O2 conditions. 5FU or SN38 were added to medium and treated for 7 days (indicated by black bars). At day 7, medium was changed to fresh StemPro hESC containing growth factors (black arrows), and CTOS samples were allowed to regrow under 20% O2. B) Representative images of CTOS samples in (A). Scale bar  =  100 µm.

Mentions: We then examined the chemo-sensitivity of CTOS in dormant status (Figure 6). CTOS samples were pre-cultured in hypoxia and growth factor–deprived conditions for 7 days. After that, they were exposed to 5FU or SN38, the active metabolite of irinotecan, for 7 days, followed by washing and culturing in fresh StemPro hESC. The CTOS samples in the dormant status showed regrowth after being returned to optimal culture conditions at a 10-fold higher dose than the CTOS samples in the active status (Figure 6A and B). These results indicated that cancer cells in the dormant state were more resistant to chemotherapies than those in an active state.


Dormancy of cancer cells with suppression of AKT activity contributes to survival in chronic hypoxia.

Endo H, Okuyama H, Ohue M, Inoue M - PLoS ONE (2014)

Primary colorectal cancer in dormant status is resistant to chemotherapy.A) CTOS samples were cultured in medium with (GF+) or without (GF−) growth factors, and under 20% O2 or 1% O2 conditions. 5FU or SN38 were added to medium and treated for 7 days (indicated by black bars). At day 7, medium was changed to fresh StemPro hESC containing growth factors (black arrows), and CTOS samples were allowed to regrow under 20% O2. B) Representative images of CTOS samples in (A). Scale bar  =  100 µm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4048292&req=5

pone-0098858-g006: Primary colorectal cancer in dormant status is resistant to chemotherapy.A) CTOS samples were cultured in medium with (GF+) or without (GF−) growth factors, and under 20% O2 or 1% O2 conditions. 5FU or SN38 were added to medium and treated for 7 days (indicated by black bars). At day 7, medium was changed to fresh StemPro hESC containing growth factors (black arrows), and CTOS samples were allowed to regrow under 20% O2. B) Representative images of CTOS samples in (A). Scale bar  =  100 µm.
Mentions: We then examined the chemo-sensitivity of CTOS in dormant status (Figure 6). CTOS samples were pre-cultured in hypoxia and growth factor–deprived conditions for 7 days. After that, they were exposed to 5FU or SN38, the active metabolite of irinotecan, for 7 days, followed by washing and culturing in fresh StemPro hESC. The CTOS samples in the dormant status showed regrowth after being returned to optimal culture conditions at a 10-fold higher dose than the CTOS samples in the active status (Figure 6A and B). These results indicated that cancer cells in the dormant state were more resistant to chemotherapies than those in an active state.

Bottom Line: ATP turnover, an indicator of energy demand, was markedly decreased and accompanied by reduced AKT phosphorylation.Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro and a decreased number of dormant cells in vivo.Primary colorectal cancer cells in dormancy were resistant to chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.

ABSTRACT
A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to recent progress in understanding the acute response of cancer cells to hypoxia, the characteristics of tumor cells in chronic hypoxia remain elusive. We have identified a pancreatic cancer cell line, AsPC-1, that is exceptionally able to survive for weeks under 1% oxygen conditions while most tested cancer cell lines die after only some days under these conditions. In chronic hypoxia, AsPC-1 cells entered a state of dormancy characterized by no proliferation, no death, and metabolic suppression. They reversibly switched to active status after being placed again in optimal culture conditions. ATP turnover, an indicator of energy demand, was markedly decreased and accompanied by reduced AKT phosphorylation. Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro and a decreased number of dormant cells in vivo. In contrast to most cancer cell lines, primary-cultured colorectal cancer cells easily entered the dormant status with AKT suppression under hypoxia combined with growth factor-depleted conditions. Primary colorectal cancer cells in dormancy were resistant to chemotherapy. Thus, the ability to survive in a deteriorated microenvironment by entering into dormancy under chronic hypoxia might be a common property among cancer cells. Targeting the regulatory mechanism inducing this dormant status could provide a new strategy for treating cancer.

Show MeSH
Related in: MedlinePlus