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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.

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Forced activation of AKT reduces the inactive zone in vivo.A) Immunohistochemistry of xenotumors of AsPC-1 cells expressing control vector (upper) or AKT-mΔPH (lower). N, necrosis; scale bar  = 100 µm. B) Percent of BrdU-positive cells in the area distal or proximal to pimonidazole-positive zone. C) Width of pimonidazole-positive zone in tumors from vector or AKT-mΔPH; *p<0.05, ***p<0.001.
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pone-0098858-g004: Forced activation of AKT reduces the inactive zone in vivo.A) Immunohistochemistry of xenotumors of AsPC-1 cells expressing control vector (upper) or AKT-mΔPH (lower). N, necrosis; scale bar  = 100 µm. B) Percent of BrdU-positive cells in the area distal or proximal to pimonidazole-positive zone. C) Width of pimonidazole-positive zone in tumors from vector or AKT-mΔPH; *p<0.05, ***p<0.001.

Mentions: We then examined the characteristics of tumors derived from AKT-mΔPH–expressing AsPC-1 cells in vivo (Figure 4). Phosphorylation of AKT was detectable only in the AKT-mΔPH tumors but not in the control tumors (Figure 4A). We observed downregulation of S6 phosphorylation and bromodeoxyuridine (BrdU) uptake in the pimonidazole-positive area and its proximal zone in control tumors, consistent with our previous report using another cancer cell line [4]. These areas suggest the existence of a zone of hypoxia-induced dormancy in vivo. In contrast, AKT-mΔPH–expressing tumors rarely contained the dormant zone in the pimonidazole-proximal region. The pS6- or BrdU-positive cells were observed even at the boundary of necrosis (Figure 4A).


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)

Forced activation of AKT reduces the inactive zone in vivo.A) Immunohistochemistry of xenotumors of AsPC-1 cells expressing control vector (upper) or AKT-mΔPH (lower). N, necrosis; scale bar  = 100 µm. B) Percent of BrdU-positive cells in the area distal or proximal to pimonidazole-positive zone. C) Width of pimonidazole-positive zone in tumors from vector or AKT-mΔPH; *p<0.05, ***p<0.001.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0098858-g004: Forced activation of AKT reduces the inactive zone in vivo.A) Immunohistochemistry of xenotumors of AsPC-1 cells expressing control vector (upper) or AKT-mΔPH (lower). N, necrosis; scale bar  = 100 µm. B) Percent of BrdU-positive cells in the area distal or proximal to pimonidazole-positive zone. C) Width of pimonidazole-positive zone in tumors from vector or AKT-mΔPH; *p<0.05, ***p<0.001.
Mentions: We then examined the characteristics of tumors derived from AKT-mΔPH–expressing AsPC-1 cells in vivo (Figure 4). Phosphorylation of AKT was detectable only in the AKT-mΔPH tumors but not in the control tumors (Figure 4A). We observed downregulation of S6 phosphorylation and bromodeoxyuridine (BrdU) uptake in the pimonidazole-positive area and its proximal zone in control tumors, consistent with our previous report using another cancer cell line [4]. These areas suggest the existence of a zone of hypoxia-induced dormancy in vivo. In contrast, AKT-mΔPH–expressing tumors rarely contained the dormant zone in the pimonidazole-proximal region. The pS6- or BrdU-positive cells were observed even at the boundary of necrosis (Figure 4A).

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