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AMPK Promotes Aberrant PGC1? Expression To Support Human Colon Tumor Cell Survival.

ABSTRACT: A major goal of cancer research is the identification of tumor-specific vulnerabilities that can be exploited for the development of therapies that are selectively toxic to the tumor. We show here that the transcriptional coactivators peroxisome proliferator-activated receptor gamma coactivator 1? (PGC1?) and estrogen-related receptor ? (ERR?) are aberrantly expressed in human colon cell lines and tumors. With kinase suppressor of Ras 1 (KSR1) depletion as a reference standard, we used functional signature ontology (FUSION) analysis to identify the ?1 subunit of AMP-activated protein kinase (AMPK) as an essential contributor to PGC1? expression and colon tumor cell survival. Subsequent analysis revealed that a subunit composition of AMPK (?2?2?1) is preferred for colorectal cancer cell survival, at least in part, by stabilizing the tumor-specific expression of PGC1?. In contrast, PGC1? and ERR? are not detectable in nontransformed human colon epithelial cells, and depletion of the AMPK?1 subunit has no effect on their viability. These data indicate that Ras oncogenesis relies on the aberrant activation of a PGC1?-dependent transcriptional pathway via a specific AMPK isoform.

SUBMITTER: Fisher KW

PROVIDER: S-EPMC4609747 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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AMPK Promotes Aberrant PGC1β Expression To Support Human Colon Tumor Cell Survival.

Fisher Kurt W KW Das Binita B Kim Hyun Seok HS Clymer Beth K BK Gehring Drew D Smith Deandra R DR Costanzo-Garvey Diane L DL Fernandez Mario R MR Brattain Michael G MG Kelly David L DL MacMillan John J White Michael A MA Lewis Robert E RE

Molecular and cellular biology 20150908 22

A major goal of cancer research is the identification of tumor-specific vulnerabilities that can be exploited for the development of therapies that are selectively toxic to the tumor. We show here that the transcriptional coactivators peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β) and estrogen-related receptor α (ERRα) are aberrantly expressed in human colon cell lines and tumors. With kinase suppressor of Ras 1 (KSR1) depletion as a reference standard, we used functiona ...[more]

PMID: 26351140

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Project description:BackgroundColorectal cancer (CRC) is one of the most prevalent and deadly tumors worldwide. The majority of CRC is resistant to anti-programmed cell death-1 (PD-1)-based cancer immunotherapy, with approximately 15% with high-microsatellite instability, high tumor mutation burden, and intratumoral lymphocytic infiltration. Programmed death-ligand 1 (PD-L1)/PD-1 signaling was described in solid tumor cells. In melanoma, liver, and thyroid cancer cells, intrinsic PD-1 signaling activates oncogenic functions, while in lung cancer cells, it has a tumor suppressor effect. Our work aimed to evaluate the effects of the anti-PD-1 nivolumab (NIVO) on CRC cells.MethodsIn vitro NIVO-treated human colon cancer cells (HT29, HCT116, and LoVo) were evaluated for cell growth, chemo/radiotherapeutic sensitivity, apoptosis, and spheroid growth. Total RNA-seq was assessed in 6-24 hours NIVO-treated human colon cancer cells HT29 and HCT116 as compared with NIVO-treated PES43 human melanoma cells. In vivo mice carrying HT29 xenograft were intraperitoneally treated with NIVO, OXA (oxaliplatin), and NIVO+OXA, and the tumors were characterized for growth, apoptosis, and pERK1/2/pP38. Forty-eight human primary colon cancers were evaluated for PD-1 expression through immunohistochemistry.ResultsIn PD-1+ human colon cancer cells, intrinsic PD-1 signaling significantly decreased proliferation and promoted apoptosis. On the contrary, NIVO promoted proliferation, reduced apoptosis, and protected PD-1+ cells from chemo/radiotherapy. Transcriptional profile of NIVO-treated HT29 and HCT116 human colon cancer cells revealed downregulation of BATF2, DRAM1, FXYD3, IFIT3, MT-TN, and TNFRSF11A, and upregulation of CLK1, DCAF13, DNAJC2, MTHFD1L, PRPF3, PSMD7, and SCFD1; the opposite regulation was described in NIVO-treated human melanoma PES43 cells. Differentially expressed genes (DEGs) were significantly enriched for interferon pathway, innate immune, cytokine-mediated signaling pathways. In vivo, NIVO promoted HT29 tumor growth, thus reducing OXA efficacy as revealed through significant Ki-67 increase, pERK1/2 and pP38 increase, and apoptotic cell reduction. Eleven out of 48 primary human colon cancer biopsies expressed PD-1 (22.9%). PD-1 expression is significantly associated with lower pT stage.ConclusionsIn PD-1+ human colon cancer cells, NIVO activates tumor survival pathways and could protect tumor cells from conventional therapies.

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AMPK Promotes Aberrant PGC1? Expression To Support Human Colon Tumor Cell Survival.

Publications

AMPK Promotes Aberrant PGC1β Expression To Support Human Colon Tumor Cell Survival.

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