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Deficiency of AMPK in CD8+ T cells suppresses their anti-tumor function by inducing protein phosphatase-mediated cell death.

Rao E, Zhang Y, Zhu G, Hao J, Persson XM, Egilmez NK, Suttles J, Li B - Oncotarget (2015)

Bottom Line: A number of studies have linked AMPK, a major metabolic sensor coordinating of multiple cellular functions, to tumor development and progression.Here we report that activation of AMPK promotes survival and anti-tumor function of T cells, in particular CD8+ T cells, resulting in superior tumor suppression in vivo.Moreover, we demonstrate that protein phosphatases are the key mediators of AMPK-dependent effects on T cell death, and inhibition of phosphatase activity by okadaic acid successfully restores T cell survival and function.

View Article: PubMed Central - PubMed

Affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.

ABSTRACT
A number of studies have linked AMPK, a major metabolic sensor coordinating of multiple cellular functions, to tumor development and progression. However, the exact role of AMPK in tumor development is still controversial. Here we report that activation of AMPK promotes survival and anti-tumor function of T cells, in particular CD8+ T cells, resulting in superior tumor suppression in vivo. While AMPK expression is dispensable for T cell development, genetic deletion of AMPK promotes T cell death during in vitro activation and in vivo tumor development. Moreover, we demonstrate that protein phosphatases are the key mediators of AMPK-dependent effects on T cell death, and inhibition of phosphatase activity by okadaic acid successfully restores T cell survival and function. Altogether, our data suggest a novel mechanism by which AMPK regulates protein phosphatase activity in control of survival and function of CD8+ T cells, thereby enhancing their role in tumor immunosurveillance.

No MeSH data available.


Related in: MedlinePlus

AMPK deficiency in T cells promotes tumor growth in miceA, E0771 cells (0.2×106) were orthotopically injected into the mammary pad of AMPK KO and WT mice (n=9/group). Tumor growth was measured at 3-day intervals. B, weight of E0771 tumor mass was analyzed on day 22 after E0771 cell implantation in mice. LL2 (0.2×106) (C) and MC38 (0.2×106) (E) cells were subcutaneously injected into the right flank of AMPK KO and WT mice (n=9/group), respectively, and tumor growth was measured at 3-day intervals. Weight of LL2 tumors (D) and MC38 tumors (F) was analyzed on day 22 after tumor cell injection. Data shown are representative of at least two independent experiments.
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Figure 2: AMPK deficiency in T cells promotes tumor growth in miceA, E0771 cells (0.2×106) were orthotopically injected into the mammary pad of AMPK KO and WT mice (n=9/group). Tumor growth was measured at 3-day intervals. B, weight of E0771 tumor mass was analyzed on day 22 after E0771 cell implantation in mice. LL2 (0.2×106) (C) and MC38 (0.2×106) (E) cells were subcutaneously injected into the right flank of AMPK KO and WT mice (n=9/group), respectively, and tumor growth was measured at 3-day intervals. Weight of LL2 tumors (D) and MC38 tumors (F) was analyzed on day 22 after tumor cell injection. Data shown are representative of at least two independent experiments.

Mentions: To investigate whether AMPK specific-deletion in T cells impacts tumor growth, we orthotopically injected mammary tumor cells E0771 into the mammary fat pad of KO mice and their WT littermates as previously described [28]. Tumor growth was monitored over a 4-week period after tumor implantation. Although mammary tumors were able to grow in both strains, tumor volume in AMPK KO mice was 2 fold larger as compared to tumors in WT mice (Figure 2A). Average tumor weight in KO mice was also 2 fold greater than that in WT mice (Figure 2B). As AMPK was only deficient in T cells, but not other populations, these results suggest that AMPK expression in T cells is critical in T cell-mediated suppression of tumor growth. To further confirm these observations, we injected other tumor cells originated from different tissues, such as LL2 (Lewis lung carcinoma) and MC38 (colon carcinoma), into these mice and monitored their growth. Consistently, tumor volume and tumor weight of all tested tumors were significantly higher in KO mice than in WT mice (Figure 2C-2F), suggesting a general anti-tumor mechanism by which T cells employ AMPK during tumor development.


Deficiency of AMPK in CD8+ T cells suppresses their anti-tumor function by inducing protein phosphatase-mediated cell death.

Rao E, Zhang Y, Zhu G, Hao J, Persson XM, Egilmez NK, Suttles J, Li B - Oncotarget (2015)

AMPK deficiency in T cells promotes tumor growth in miceA, E0771 cells (0.2×106) were orthotopically injected into the mammary pad of AMPK KO and WT mice (n=9/group). Tumor growth was measured at 3-day intervals. B, weight of E0771 tumor mass was analyzed on day 22 after E0771 cell implantation in mice. LL2 (0.2×106) (C) and MC38 (0.2×106) (E) cells were subcutaneously injected into the right flank of AMPK KO and WT mice (n=9/group), respectively, and tumor growth was measured at 3-day intervals. Weight of LL2 tumors (D) and MC38 tumors (F) was analyzed on day 22 after tumor cell injection. Data shown are representative of at least two independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4480727&req=5

Figure 2: AMPK deficiency in T cells promotes tumor growth in miceA, E0771 cells (0.2×106) were orthotopically injected into the mammary pad of AMPK KO and WT mice (n=9/group). Tumor growth was measured at 3-day intervals. B, weight of E0771 tumor mass was analyzed on day 22 after E0771 cell implantation in mice. LL2 (0.2×106) (C) and MC38 (0.2×106) (E) cells were subcutaneously injected into the right flank of AMPK KO and WT mice (n=9/group), respectively, and tumor growth was measured at 3-day intervals. Weight of LL2 tumors (D) and MC38 tumors (F) was analyzed on day 22 after tumor cell injection. Data shown are representative of at least two independent experiments.
Mentions: To investigate whether AMPK specific-deletion in T cells impacts tumor growth, we orthotopically injected mammary tumor cells E0771 into the mammary fat pad of KO mice and their WT littermates as previously described [28]. Tumor growth was monitored over a 4-week period after tumor implantation. Although mammary tumors were able to grow in both strains, tumor volume in AMPK KO mice was 2 fold larger as compared to tumors in WT mice (Figure 2A). Average tumor weight in KO mice was also 2 fold greater than that in WT mice (Figure 2B). As AMPK was only deficient in T cells, but not other populations, these results suggest that AMPK expression in T cells is critical in T cell-mediated suppression of tumor growth. To further confirm these observations, we injected other tumor cells originated from different tissues, such as LL2 (Lewis lung carcinoma) and MC38 (colon carcinoma), into these mice and monitored their growth. Consistently, tumor volume and tumor weight of all tested tumors were significantly higher in KO mice than in WT mice (Figure 2C-2F), suggesting a general anti-tumor mechanism by which T cells employ AMPK during tumor development.

Bottom Line: A number of studies have linked AMPK, a major metabolic sensor coordinating of multiple cellular functions, to tumor development and progression.Here we report that activation of AMPK promotes survival and anti-tumor function of T cells, in particular CD8+ T cells, resulting in superior tumor suppression in vivo.Moreover, we demonstrate that protein phosphatases are the key mediators of AMPK-dependent effects on T cell death, and inhibition of phosphatase activity by okadaic acid successfully restores T cell survival and function.

View Article: PubMed Central - PubMed

Affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.

ABSTRACT
A number of studies have linked AMPK, a major metabolic sensor coordinating of multiple cellular functions, to tumor development and progression. However, the exact role of AMPK in tumor development is still controversial. Here we report that activation of AMPK promotes survival and anti-tumor function of T cells, in particular CD8+ T cells, resulting in superior tumor suppression in vivo. While AMPK expression is dispensable for T cell development, genetic deletion of AMPK promotes T cell death during in vitro activation and in vivo tumor development. Moreover, we demonstrate that protein phosphatases are the key mediators of AMPK-dependent effects on T cell death, and inhibition of phosphatase activity by okadaic acid successfully restores T cell survival and function. Altogether, our data suggest a novel mechanism by which AMPK regulates protein phosphatase activity in control of survival and function of CD8+ T cells, thereby enhancing their role in tumor immunosurveillance.

No MeSH data available.


Related in: MedlinePlus