Inhibition of LPAR6 overcomes sorafenib resistance by switching glycolysis into oxidative phosphorylation in hepatocellular carcinoma

Gnocchi, Davide; Kurzyk, Agata; Mintrone, Antonella; Lentini, Giovanni; Sabbá, Carlo; Mazzocca, Antonio

doi:10.1016/j.biochi.2022.07.016

Cited by 13 publications

(10 citation statements)

References 48 publications

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“…In the process of energy metabolic switch, the M2 isoform of pyruvate kinase (PKM2, a rate-limiting enzyme in glycolysis) interacts with the key regulator of mitochondrial fusion protein MFN2 to promote the mitochondria fusion and OXPHOS, meanwhile attenuate glycolysis 62 , consistently, the activation of MFN2 interacting with PFK1 mediate PFK1 degradation and therefore suppresses glycolysis 63 . In Hepatocellular carcinoma (HCC), inhibition of lysophosphatidic acid receptor 6 (LPAR6) overcomes sorafenib resistance by switching glycolysis into OXPHOS 64 . Moreover, the cancer suppressor gene p53 suppresses glycolysis and promotes mitochondria oxidative phosphorylation by a series of downstream targets against the Warburg effect 65 .…”

Section: Mitochondrial Function In Cancer Cell Metabolismmentioning

confidence: 99%

An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

Liu¹,

Sun²,

Guo³

et al. 2023

Int. J. Biol. Sci.

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Mitochondria are intracellular organelles involved in energy production, cell metabolism and cell signaling. They are essential not only in the process of ATP synthesis, lipid metabolism and nucleic acid metabolism, but also in tumor development and metastasis. Mutations in mtDNA are commonly found in cancer cells to promote the rewiring of bioenergetics and biosynthesis, various metabolites especially oncometabolites in mitochondria regulate tumor metabolism and progression. And mutation of enzymes in the TCA cycle leads to the unusual accumulation of certain metabolites and oncometabolites. Mitochondria have been demonstrated as the target for cancer treatment. Cancer cells rely on two main energy resources: oxidative phosphorylation (OXPHOS) and glycolysis. By manipulating OXPHOS genes or adjusting the metabolites production in mitochondria, tumor growth can be restrained. For example, enhanced complex I activity increases NAD + /NADH to prevent metastasis and progression of cancers. In this review, we discussed mitochondrial function in cancer cell metabolism and specially explored the unique role of mitochondria in cancer stem cells and the tumor microenvironment. Targeting the OXPHOS pathway and mitochondria-related metabolism emerging as a potential therapeutic strategy for various cancers.

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Section: Mitochondrial Function In Cancer Cell Metabolismmentioning

confidence: 99%

An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

Liu¹,

Sun²,

Guo³

et al. 2023

Int. J. Biol. Sci.

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“…In this regard, plant extracts may be considered as a valuable option due to their blended composition, which can target several processes at the same time. Coupled with this approach, selective inhibition of specific metabolism-controlling receptors may provide a supplemental option, as described above for LPAR6 [130,158].…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

“…While pharmacological ETC inhibitors reduce mitochondrial respiration and induce apoptosis in cancer cells, cancer cells modulate their metabolism, shifting to a glycolytic mode and resulting in a drugresistant phenotype [129]. We recently showed how to overcome sorafenib resistance in hepatocellular carcinoma by switching glycolysis to OXPHOS [130]. This could support the use of combination therapies to enhance the efficacy of conventional therapies, as well as the development of new rationally designed combinations [131].…”

Section: Targeting Energy Metabolism and The Microenvironment In Canc...mentioning

confidence: 99%

Cellular Adaptation Takes Advantage of Atavistic Regression Programs during Carcinogenesis

Gnocchi,

Nikolic,

Paparella

et al. 2023

Cancers

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Adaptation of cancer cells to extreme microenvironmental conditions (i.e., hypoxia, high acidity, and reduced nutrient availability) contributes to cancer resilience. Furthermore, neoplastic transformation can be envisioned as an extreme adaptive response to tissue damage or chronic injury. The recent Systemic–Evolutionary Theory of the Origin of Cancer (SETOC) hypothesizes that cancer cells “revert” to “primitive” characteristics either ontogenically (embryo-like) or phylogenetically (single-celled organisms). This regression may confer robustness and maintain the disordered state of the tissue, which is a hallmark of malignancy. Changes in cancer cell metabolism during adaptation may also be the consequence of altered microenvironmental conditions, often resulting in a shift toward lactic acid fermentation. However, the mechanisms underlying the robust adaptive capacity of cancer cells remain largely unknown. In recent years, cancer cells’ metabolic flexibility has received increasing attention among researchers. Here, we focus on how changes in the microenvironment can affect cancer cell energy production and drug sensitivity. Indeed, changes in the cellular microenvironment may lead to a “shift” toward “atavistic” biologic features, such as the switch from oxidative phosphorylation (OXPHOS) to lactic acid fermentation, which can also sustain drug resistance. Finally, we point out new integrative metabolism-based pharmacological approaches and potential biomarkers for early detection.

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“…In this respect, we have recently demonstrated that LPA receptor 6 (LPAR6) is directly involved in the control of HCC cell metabolism [ 155 ] and that ectopic expression of LPAR6 in HCC cells drives sorafenib resistance by triggering a “metabolic switch”, which increases lactic acid fermentation at the expense of OXPHOS. This sorafenib resistance can be overcome by reducing lactic acid fermentation through inhibition of LPAR6 using our recently developed novel LPAR6 antagonists [ 156 , 157 , 158 ]. LPAR6 has a pro-tumorigenic role in HCC [ 159 ] by controlling the trans-differentiation of peritumoral tissue fibroblasts (PTFs) into carcinoma-associated fibroblasts (CAFs) [ 160 ] and its overexpression leads to a worse clinical outcome in HCC patients [ 159 ].…”

Section: Multitarget Metabolic Systemsmentioning

confidence: 99%

“…Furthermore, it is worth mentioning that, in our opinion, modulating the balance between OXPHOS and lactic acid fermentation to trigger OXPHOS and inhibit fermentation could be considered a strategy to reduce tumor invasiveness and drug resistance. Indeed, we recently demonstrated that inhibition of OXPHOS in favor of lactic acid fermentation elicits drug resistance in HCC [ 156 ]. Based on this observation, approaches to modulate the metabolism of fermenting tumor cells may provide tools to overcome cancer drug resistance.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Metabolism as a New Avenue for Hepatocellular Carcinoma Therapy

Gnocchi

Sabbá

Massimi

et al. 2023

IJMS

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Hepatocellular carcinoma is today the sixth leading cause of cancer-related death worldwide, despite the decreased incidence of chronic hepatitis infections. This is due to the increased diffusion of metabolic diseases such as the metabolic syndrome, diabetes, obesity, and nonalcoholic steatohepatitis (NASH). The current protein kinase inhibitor therapies in HCC are very aggressive and not curative. From this perspective, a shift in strategy toward metabolic therapies may represent a promising option. Here, we review current knowledge on metabolic dysregulation in HCC and therapeutic approaches targeting metabolic pathways. We also propose a multi-target metabolic approach as a possible new option in HCC pharmacology.

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Inhibition of LPAR6 overcomes sorafenib resistance by switching glycolysis into oxidative phosphorylation in hepatocellular carcinoma

Cited by 13 publications

References 48 publications

An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

Cellular Adaptation Takes Advantage of Atavistic Regression Programs during Carcinogenesis

Metabolism as a New Avenue for Hepatocellular Carcinoma Therapy

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