AMPK-mediated energy homeostasis and associated metabolic effects on cancer cell response and resistance to cetuximab

Li, Xinqun; Lü, Yang; Lu, Haiquan; Luo, Jingtao; Hong, Yun; Fan, Zhen

doi:10.18632/oncotarget.3432

Cited by 28 publications

(27 citation statements)

References 51 publications

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“…The LIVE/DEAD cell viability assay kit (Life Technologies) was used to detect cell death as we recently described [30]. In brief, following treatment, cells were incubated with 4 µM calcein acetoxymethyl ester and 2 µM ethidium homodimer-1 together in a 37°C, 5% CO 2 incubator for 45 minutes.…”

Section: Methodsmentioning

confidence: 99%

Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism

et al. 2016

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Cisplatin is currently one of the most effective chemotherapeutic drugs used for treating ovarian cancer; however, resistance to cisplatin is common. In this study, we explored an experimental strategy for overcoming cisplatin resistance of human ovarian cancer from the new perspective of cancer cell metabolism. By using two pairs of genetically matched cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines, we tested the hypothesis that downregulating hypoxia-inducible factor-1 (HIF-1), which regulates metabolic enzymes involved in glycolysis, is a promising strategy for overcoming cisplatin resistance of human ovarian cancer cells. We found that cisplatin downregulated the level of the regulatable α subunit of HIF-1, HIF-1α, in cisplatin-sensitive ovarian cancer cells through enhancing HIF-1α degradation but did not downregulate HIF-1α in their cisplatin-resistant counterparts. Overexpression of a degradation-resistant HIF-1α (HIF-1α ΔODD) reduced cisplatin-induced apoptosis in cisplatin-sensitive cells, whereas genetic knockdown of HIF-1α or pharmacological promotion of HIF-1α degradation enhanced response to cisplatin in both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. We further demonstrated that knockdown of HIF-1α improved the response of cisplatin-resistant ovarian cancer cells to cisplatin by redirecting the aerobic glycolysis in the resistant cancer cells towards mitochondrial oxidative phosphorylation, leading to cell death through overproduction of reactive oxygen species. Our findings suggest that the HIF-1α-regulated cancer metabolism pathway could be a novel target for overcoming cisplatin resistance in ovarian cancer.

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Section: Methodsmentioning

confidence: 99%

Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism

et al. 2016

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“…The procedure for Western blotting was previously described [8,11]. The primary antibodies used for Western blotting and their sources were as follows: HIF-1α and SREBP-1c, BD Biosciences; T172-phosphorylated AMPK, AMPK, S79-phosphorylated ACC1, ACC1, ACC2, and FASN, Cell Signaling Technology; and β-actin, Sigma-Aldrich.…”

Section: Methodsmentioning

confidence: 99%

“…More recently, we reported that inhibition of HIF-1 transcriptional activity by cetuximab does not always lead to successful inhibition of cell proliferation [11]. In human head and neck squamous cell carcinoma (HNSCC) cells, we observed that the response to cetuximab-mediated growth inhibition was linked to the activity status of the cell energy sensor AMP-activated protein kinase (AMPK).…”

Section: Introductionmentioning

confidence: 99%

“…HNSCC cells with a low basal level of AMPK activity were more sensitive to cetuximab-induced growth inhibition and exhibited a transient activation of AMPK after cetuximab treatment. In contrast, HNSCC cells with a high basal level of AMPK activity were less sensitive to cetuximab-induced growth inhibition despite effective inhibition of EGFR downstream signaling by cetuximab [11]. …”

Section: Introductionmentioning

confidence: 99%

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Acetyl-CoA carboxylase rewires cancer metabolism to allow cancer cells to survive inhibition of the Warburg effect by cetuximab

et al. 2017

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Cetuximab inhibits HIF-1-regulated glycolysis in cancer cells, thereby reversing the Warburg effect and leading to inhibition of cancer cell metabolism. AMP-activated protein kinase (AMPK) is activated after cetuximab treatment, and a sustained AMPK activity is a mechanism contributing to cetuximab resistance. Here, we investigated how acetyl-CoA carboxylase (ACC), a downstream target of AMPK, rewires cancer metabolism in response to cetuximab treatment. We found that introduction of experimental ACC mutants lacking the AMPK phosphorylation sites (ACC1_S79A and ACC2_S212A) into head and neck squamous cell carcinoma (HNSCC) cells protected HNSCC cells from cetuximab-induced growth inhibition. HNSCC cells with acquired cetuximab resistance contained not only high levels of T172-phosphorylated AMPK and S79-phosphorylated ACC1 but also an increased level of total ACC. These findings were corroborated in tumor specimens of HNSCC patients treated with cetuximab. Cetuximab plus TOFA (an allosteric inhibitor of ACC) achieved remarkable growth inhibition of cetuximab-resistant HNSCC xenografts. Our data suggest a novel paradigm in which cetuximab-mediated activation of AMPK and subsequent phosphorylation and inhibition of ACC is followed by a compensatory increase in total ACC, which rewires cancer metabolism from glycolysis-dependent to lipogenesis-dependent.

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“…(15,114,115). Even though mitochondrial respiration is identified as a predominant biologic function of PGC1a in cancer, a few studies also underscore PGC1a as a promoter of FAO and glucose-or glutaminederived lipogenesis in recent years (49,51,58).…”

Section: Conclusion and Further Perspectivesmentioning

confidence: 99%

The Role of PGC1α in Cancer Metabolism and its Therapeutic Implications

Tan

Luo

Xiao

et al. 2016

Molecular Cancer Therapeutics

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AMPK-mediated energy homeostasis and associated metabolic effects on cancer cell response and resistance to cetuximab

Cited by 28 publications

References 51 publications

Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism

Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism

Acetyl-CoA carboxylase rewires cancer metabolism to allow cancer cells to survive inhibition of the Warburg effect by cetuximab

The Role of PGC1α in Cancer Metabolism and its Therapeutic Implications

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