Gain of HIF-1α under Normoxia in Cancer Mediates Immune Adaptation through the AKT/ERK and VEGFA Axes

Lee, Young Ho; Bae, Hyun Cheol; Noh, Kyung Hee; Song, Kwon Ho; Ye, Sang Kyu; Mao, Chih Ping; Lee, Kyung Mi; Wu, T. C.; Kim, Tae Woo

doi:10.1158/1078-0432.ccr-14-1979

Cited by 50 publications

(48 citation statements)

References 25 publications

(25 reference statements)

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“…This was accompanied by a loss of signaling of other oncogenic components, AKT/ERK and VEGF ( Figure 7, C and D). Antioxidant infusion did not further reduce the level of AKT/ERK signaling in P3 cells transfected with siHif1a or siHIF1A (Supplemental Figure 9), suggesting that ROS mediate AKT/ERK signaling through the expression of HIF-1, as reported previously (28).…”

Section: Loss Of Atp Synthase Activates the Hif-1 Pathway Through Rossupporting

confidence: 81%

“…For this, we subjected mouse or human tumor cells transformed with HPV oncoproteins (TC-1 or CaSki, respectively) to 3 rounds of in vivo or in vitro selection by cognate CTLs, respectively, as described previously (18,28). At the end of the selection process, the tumor cells (termed P3) were refractory to apoptotic death by cognate CTLs, whereas the parental cells (termed P0), or tumor cells mixed for 3 rounds with noncognate T cells, remained sensitive to cognate CTLs (18,28). We compared the susceptibility of P3 versus P0 cells to various classes of chemotherapy or radiotherapy.…”

Section: Resultsmentioning

confidence: 99%

“…In this regard, we have found that expression of HIF-1α is profoundly upregulated -under both normoxia and hypoxia -in tumor cells subjected to immune editing by tumor-specific CTLs compared with those without selection (28). While we have established that the HIF-1α/VEGF axis drives immune escape (28), it is unclear how HIF-1α protein expression is induced in tumor cells under immune editing. Our present study demonstrated that ATP5H loss-mediated mitochondrial dysfunction could accumulate ROS, which in turn stabilized HIF-1α in normoxic conditions.…”

Section: Loss Of Atp Synthase Activates the Hif-1 Pathway Through Rosmentioning

confidence: 99%

“…+ TC-1 cells (P0, P1, P2, P3) and CaSki cells (P0, P1, P2, P3) have been described previously (18,28 Mice. Six-to eight-week-old female C57BL/6 and NOD/SCID mice were purchased from Central Lab Animal Inc.…”

Section: Cells the Production And Maintenance Of Hpv-16 E7mentioning

confidence: 99%

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Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance

Song¹,

Kim²,

Lee³

et al. 2018

Journal of Clinical Investigation

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The host immune system plays a pivotal role in the emergence of tumor cells that are refractory to multiple clinical interventions including immunotherapy, chemotherapy, and radiotherapy. Here, we examined the molecular mechanisms by which the immune system triggers cross-resistance to these interventions. By examining the biological changes in murine and tumor cells subjected to sequential rounds of in vitro or in vivo immune selection via cognate cytotoxic T lymphocytes, we found that multimodality resistance arises through a core metabolic reprogramming pathway instigated by epigenetic loss of the ATP synthase subunit ATP5H, which leads to ROS accumulation and HIF-1α stabilization under normoxia. Furthermore, this pathway confers to tumor cells a stem-like and invasive phenotype. In vivo delivery of antioxidants reverses these phenotypic changes and resensitizes tumor cells to therapy. ATP5H loss in the tumor is strongly linked to failure of therapy, disease progression, and poor survival in patients with cancer. Collectively, our results reveal a mechanism underlying immune-driven multimodality resistance to cancer therapy and demonstrate that rational targeting of mitochondrial metabolic reprogramming in tumor cells may overcome this resistance. We believe these results hold important implications for the clinical management of cancer.

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Section: Loss Of Atp Synthase Activates the Hif-1 Pathway Through Rossupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Loss Of Atp Synthase Activates the Hif-1 Pathway Through Rosmentioning

confidence: 99%

Section: Cells the Production And Maintenance Of Hpv-16 E7mentioning

confidence: 99%

See 2 more Smart Citations

Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance

Song¹,

Kim²,

Lee³

et al. 2018

Journal of Clinical Investigation

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“…Normoxic and hypoxic stabilization of HIF signaling in tumor cells promotes resistance to cytotoxic T lymphocyte–mediated lysis ( 51–54 ). Hypoxia and HIF-mediated activation of autophagy in tumor cells also regulates natural killer (NK) cell–mediated antitumor responses; this occurs through the hypoxic degradation of NK-derived granzyme B in autophagosomes and the induction of inositol 1,4,5-trisphosphate receptor, type 1 ( 55, 56 ).…”

Section: Mechanisms Of Hif-mediated Metastasismentioning

confidence: 99%

Hypoxic control of metastasis

Rankin

Giaccia

2016

Science

1,013

870

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Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Hypoxia is a potent microenvironmental factor promoting metastatic progression. Clinically, hypoxia and the expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 are associated with increased distant metastasis and poor survival in a variety of tumor types. Moreover, HIF signaling in malignant cells influences multiple steps within the metastatic cascade. Here we review research focused on elucidating the mechanisms by which the hypoxic tumor microenvironment promotes metastatic progression. These studies have identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at preventing and treating metastatic disease.

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The role of hypoxia‐inducible factor 1 in tumor immune evasion

Wang

et al. 2020

Medicinal Research Reviews

185

146

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Hypoxia‐inducible factor 1 (HIF‐1) plays an indispensable role in the hypoxic tumor microenvironment. Hypoxia and HIF‐1 are involved in multiple aspects of tumor progression, such as metastasis, angiogenesis, and immune evasion. In innate and adaptive immune systems, malignant tumor cells avoid their recognition and destruction by HIF‐1. Tumor immune evasion allows cancer cells to proliferate and metastasize and is associated with immunotherapy failure and chemoresistance. In the hypoxic tumor microenvironment, HIF‐1 signaling suppresses the innate and adaptive immune systems to evade immune attack by inducing the expression of immunosuppressive factors and immune checkpoint molecules, including vascular endothelial growth factor, prostaglandin E2, and programmed death‐ligand 1/programmed death‐1. Moreover, HIF‐1 blocks tumor‐associated antigen presentation via major histocompatibility complex class I chain‐related/natural killer group 2, member D signaling. Tumor‐associated autophagy and the release of tumor‐derived exosomes contribute to HIF‐1‐mediated immune evasion. This review focuses on recent findings on the potential mechanism(s) underlying the effect of hypoxia and HIF‐1 signaling on tumor immune evasion in the hypoxic tumor microenvironment. The effects of HIF‐1 on immune checkpoint molecules, immunosuppressive molecules, autophagy, and exosomes have been described. Additionally, the potential role of HIF‐1 in the regulation of tumor‐derived exosomes, as well as the roles of HIF‐1 and exosomes in tumor evasion, are discussed. This study will contribute to our understanding of HIF‐1‐mediated tumor immune evasion, leading to the development of effective HIF‐1‐targeting drugs and immunotherapies.

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Gain of HIF-1α under Normoxia in Cancer Mediates Immune Adaptation through the AKT/ERK and VEGFA Axes

Cited by 50 publications

References 25 publications

Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance

Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance

Hypoxic control of metastasis

The role of hypoxia‐inducible factor 1 in tumor immune evasion

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