PKCλ/ι Loss Induces Autophagy, Oxidative Phosphorylation, and NRF2 to Promote Liver Cancer Progression

Kudo, Yotaro; Sugimoto, Masayuki; Arias, Esperanza; Kasashima, Hiroaki; Cordes, Thekla; Linares, Juan F.; Durán, Abraham Madroñal; Nakanishi, Yuki; Nakanishi, Naoko; L’Hermitte, Antoine; Campos, Alex; Senni, Nadia; Rooslid, Tarmo; Roberts, Lewis R.; Cuervo, Ana María; Metallo, Christian M.; Karin, Michael; Diaz-Meco, Marı́a T.; Moscat, Jorge

doi:10.1016/j.ccell.2020.05.018

Cited by 79 publications

(60 citation statements)

References 41 publications

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“…Indeed, Nrf2 promoted cell survival by inducing transcription of the anti-apoptotic proteins Bcl-2 [ 111 ] and Bcl-xL, and downregulation of the pro-apoptotic factors, Bax and caspase 3/7 [ 112 ]. In agreement with these studies, caspase-3 activity has been shown to significantly increase upon Nrf2 loss [ 113 ], further supporting the notion that Nrf2 has a role in controlling survival.…”

Section: Nrf2 and Hepatocellular Carcinoma (Hcc)supporting

confidence: 77%

Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases

Orrù

Giordano

Columbano

2020

Cancers

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Activation of the Keap1/Nrf2 pathway, the most important cell defense signal, triggered to neutralize the harmful effects of electrophilic and oxidative stress, plays a crucial role in cell survival. Therefore, its ability to attenuate acute and chronic liver damage, where oxidative stress represents the key player, is not surprising. On the other hand, while Nrf2 promotes proliferation in cancer cells, its role in non-neoplastic hepatocytes is a matter of debate. Another topic of uncertainty concerns the nature of the mechanisms of Nrf2 activation in hepatocarcinogenesis. Indeed, it remains unclear what is the main mechanism behind the sustained activation of the Keap1/Nrf2 pathway in hepatocarcinogenesis. This raises doubts about the best strategies to therapeutically target this pathway. In this review, we will analyze and discuss our present knowledge concerning the role of Nrf2 in hepatic physiology and pathology, including hepatocellular carcinoma. In particular, we will critically examine and discuss some findings originating from animal models that raise questions that still need to be adequately answered.

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Section: Nrf2 and Hepatocellular Carcinoma (Hcc)supporting

confidence: 77%

Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases

Orrù

Giordano

Columbano

2020

Cancers

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“…Animal models are also important as they are able to challenge tenets stemming from the literature. As an example, in spite of a large body of evidence indicating that metabolic reprogramming from OXPHOS to Warburg phenotype is a common feature of HCC, very recent studies with KO mice implicate that enhanced OXPHOS may play a key role in HCC progression [ 146 ]. The fact that enhanced OXPHOS occurs concomitantly with Nrf2 activation–a transcription factor that is known to redirect oxidative metabolism towards a Warburg phenotype–represents a relevant exception to the general concept of metabolic reprogramming and poses the question as to whether increased glucose uptake and activation of PPP can be induced concomitantly with enhanced mitochondrial respiration.…”

Section: Discussionmentioning

confidence: 99%

“…The discovery of specific Nrf2 inhibitors, unfortunately lacking at present, will help to better elucidate the role of this transcription factor in HCC development and, hopefully, to efficiently impair the Nrf2-dependent metabolic reprogramming of neoplastic hepatocytes. The need for such studies becomes extremely urgent also on the basis of a very recent study [ 146 ] showing that the loss of protein kinase Cλ/ι (PKCλ/ι) promotes HCC by enhancing OXPHOS, in spite of activation of Nrf2—which, according to the literature, is known to redirect metabolism towards glycolysis [ 146 ].…”

Section: Mouse Models Of Hccmentioning

confidence: 99%

Animal Models: A Useful Tool to Unveil Metabolic Changes in Hepatocellular Carcinoma

Serra

Columbano

Perra

et al. 2020

Cancers

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Hepatocellular carcinoma (HCC) is one the most frequent and lethal human cancers. At present, no effective treatment for advanced HCC exist; therefore, the overall prognosis for HCC patients remains dismal. In recent years, a better knowledge of the signaling pathways involved in the regulation of HCC development and progression, has led to the identification of novel potential targets for therapeutic strategies. However, the obtained benefits from current therapeutic options are disappointing. Altered cancer metabolism has become a topic of renewed interest in the last decades, and it has been included among the core hallmarks of cancer. In the light of growing evidence for metabolic reprogramming in cancer, a wide number of experimental animal models have been exploited to study metabolic changes characterizing HCC development and progression and to further expand our knowledge of this tumor. In the present review, we discuss several rodent models of hepatocarcinogenesis, that contributed to elucidate the metabolic profile of HCC and the implications of these changes in modulating the aggressiveness of neoplastic cells. We also highlight the apparently contrasting results stemming from different animal models. Finally, we analyze whether these observations could be exploited to improve current therapeutic strategies for HCC.

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“…Here, we describe a syngeneic orthotopic HCC model that recapitulates the role of a host pro-tumorigenic microenvironment by pre-conditioning mouse livers with a high-fat diet (HFD). For complete details on the use and execution of this protocol, please refer to Kudo et al. (2020 ).…”

mentioning

confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Kudo et al. (2020 ).…”

mentioning

confidence: 99%

An Orthotopic Implantation Mouse Model of Hepatocellular Carcinoma with Underlying Liver Steatosis

et al. 2020

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Summary This protocol provides the steps required for a mouse liver orthotopic implantation model. The reliable pre-clinical animal models that have similar characteristics to hepatocellular carcinoma (HCC) are a powerful tool to unveil the mechanisms controlling tumor initiation and progression. Here, we describe a syngeneic orthotopic HCC model that recapitulates the role of a host pro-tumorigenic microenvironment by pre-conditioning mouse livers with a high-fat diet (HFD). For complete details on the use and execution of this protocol, please refer to Kudo et al. (2020 ).

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PKCλ/ι Loss Induces Autophagy, Oxidative Phosphorylation, and NRF2 to Promote Liver Cancer Progression

Cited by 79 publications

References 41 publications

Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases

Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases

Animal Models: A Useful Tool to Unveil Metabolic Changes in Hepatocellular Carcinoma

An Orthotopic Implantation Mouse Model of Hepatocellular Carcinoma with Underlying Liver Steatosis

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