Liver kinase B1/adenosine monophosphate‑activated protein kinase signaling axis induces p21/WAF1 expression in a p53‑dependent manner

Ma, Qing; Xiao, Ping; Sun, Linlin; Wang, Jing; Zhong, Diansheng

doi:10.3892/ol.2018.8741

Cited by 4 publications

(3 citation statements)

References 22 publications

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“…We found, indeed, a concomitant increase of P53 phosphorylation level in A375 and SK-Mel-28 but not in FO-1 melanoma cells. The activation of AMPK by phosphorylation, as we showed in Figure 4 , can also participate in P21 induction, as previously reported by Ma et al and Petti et al [ 61 , 62 ].…”

Section: Discussionsupporting

confidence: 87%

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

Cardile

Zanrè

Campagnari

et al. 2023

IJMS

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Hyperforin (HPF), the main component responsible for the antidepressant action of Hypericum perforatum, displays additional beneficial properties including anti-inflammatory, antimicrobic, and antitumor activities. Among its antitumor effects, HPF activity on melanoma is poorly documented. Melanoma, especially BRAF-mutated melanoma, is still a high-mortality tumor type and the currently available therapies do not provide solutions. We investigated HPF’s antimelanoma effectiveness in A375, FO1 and SK-Mel-28 human BRAF-mutated cell lines. Cell viability assays documented that all melanoma cells were affected by low HPF concentrations (EC50% 2–4 µM) in a time-dependent manner. A Br-deoxy-uridine incorporation assay attested a significant reduction of cell proliferation accompanied by decreased expression of cyclin D1 and A2, CDK4 and of the Rb protein phosphorylation, as assessed by immunoblots. In addition, the expression of P21/waf1 and the activated form of P53 were increased in A375 and SK-Mel-28 cells. Furthermore, HPF exerts cytotoxic effects. Apoptosis is induced 24 h after HPF administration, documented by an increase of cleaved-PARP1 and a decrease of both Bcl2 and Bcl-xL expression levels. Autophagy is induced, attested by an augmented LC3B expression and augmentation of the activated form of AMPK. Moreover, HPF lowers GPX4 enzyme expression, suggesting ferroptosis induction. HPF has been reported to activate the TRPC6 Ca++ channel and/or Ca++ and Zn++ release from mitochondria stores, increasing cytosolic Ca++ and Zn++ concentrations. Our data highlighted that HPF affects many cell-signaling pathways, including signaling induced by Ca++, such as FRA1, pcJun and pCREB, the expression or activity of which are increased shortly after treatment. However, the blockage of the TRPC6 Ca++ channel or the use of Ca++ and Zn++ chelators do not hinder HPF cytostatic/cytotoxic activity, suggesting that damages induced in melanoma cells may pass through other pathways. Remarkably, 24 h after HPF treatment, the expression of activated forms of the transcription factors NF-κB P65 subunit and STAT3 are significantly lowered. Several cytosolic (PGM2, LDHA and pPKM2) and mitochondrial (UQCRC1, COX4 and ATP5B) enzymes are downregulated by HPF treatment, suggesting a generalized reduction of vital functions in melanoma cells. In line with these results is the recognized ability of HPF to affect mitochondrial membrane potential by acting as a protonophore. Finally, HPF can hinder both melanoma cell migration and colony formation in soft agar. In conclusion, we provide evidence of the pleiotropic antitumor effects induced by HPF in melanoma cells.

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Section: Discussionsupporting

confidence: 87%

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

Cardile

Zanrè

Campagnari

et al. 2023

IJMS

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“…The activation of AMPK induces the expression of p21/WAF1. This increase of p21/WAF1 may be the underlying mechanism of growth arrest when cancer cells are exposed to energy stresses and ATP depletion [17].…”

Section: Upregulation Of Oxphos In Cancer Cells Drives Cellular Bioenergeticsmentioning

confidence: 99%

Mitochondria Targeting as an Effective Strategy for Cancer Therapy

Ghosh

Vidal

Dey

et al. 2020

IJMS

181

121

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Mitochondria are well known for their role in ATP production and biosynthesis of macromolecules. Importantly, increasing experimental evidence points to the roles of mitochondrial bioenergetics, dynamics, and signaling in tumorigenesis. Recent studies have shown that many types of cancer cells, including metastatic tumor cells, therapy-resistant tumor cells, and cancer stem cells, are reliant on mitochondrial respiration, and upregulate oxidative phosphorylation (OXPHOS) activity to fuel tumorigenesis. Mitochondrial metabolism is crucial for tumor proliferation, tumor survival, and metastasis. Mitochondrial OXPHOS dependency of cancer has been shown to underlie the development of resistance to chemotherapy and radiotherapy. Furthermore, recent studies have demonstrated that elevated heme synthesis and uptake leads to intensified mitochondrial respiration and ATP generation, thereby promoting tumorigenic functions in non-small cell lung cancer (NSCLC) cells. Also, lowering heme uptake/synthesis inhibits mitochondrial OXPHOS and effectively reduces oxygen consumption, thereby inhibiting cancer cell proliferation, migration, and tumor growth in NSCLC. Besides metabolic changes, mitochondrial dynamics such as fission and fusion are also altered in cancer cells. These alterations render mitochondria a vulnerable target for cancer therapy. This review summarizes recent advances in the understanding of mitochondrial alterations in cancer cells that contribute to tumorigenesis and the development of drug resistance. It highlights novel approaches involving mitochondria targeting in cancer therapy.

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“…The p21 protein is encoded by the WAF1/CIP1 suppressor gene, induced by oncoprotein p53, a wild-type TP53 gene product, and is involved in inhibiting the cell cycle between G1/S phases. Its contribution to the regulation of DNA repair and replication, as well as apoptosis modulation, has been proven [1][2][3]. After DNA damage, p21 induced by p53, either leads to cell cycle arrest or it can evoke cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

P21 is not a prognostic marker for rectal cancer – five-year follow up study of rectal cancer in stages I–IV

Kozłowska-Geller

Głuszek

Lewitowicz

2020

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Liver kinase B1/adenosine monophosphate‑activated protein kinase signaling axis induces p21/WAF1 expression in a p53‑dependent manner

Cited by 4 publications

References 22 publications

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

Mitochondria Targeting as an Effective Strategy for Cancer Therapy

P21 is not a prognostic marker for rectal cancer – five-year follow up study of rectal cancer in stages I–IV

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