Evaluation Of The Role Of Melatonin In The Metastasis Of Papillary Thyroid Carcinoma

[S.Seneff]

Article in Chinese; Abstract available in Chinese from the publisher]
Fan L1, Xiong YP1, Liu HT1, Min X1, Tang YQ1, Zhang ZY1.
Author information
1
Department of Otolaryngology Head and Neck Surgery，First Affiliated Hospital of Nanchang University，Nanchang，330006，China.
Abstract
in English, Chinese
Objective:To evaluate the level of melatonin and the role of melatonin in the metastasis of papillary thyroid carcinoma in patients with papillary thyroid carcinoma. Method:We measured serum melatonin levels in 81 patients with papillary thyroid carcinoma（PTC） ,20 patients with multinodular goiter（MNG） and 20 healthy adults using ELISA. The relationship between melatonin and clinicopathological features of PTC were analyzed.The expression of MT1 and MT2 in two subtypes of melatonin receptor in 81 cases of papillary thyroid carcinoma and adjacent tissues were detected by immunohistochemical SP method, and its the mean optical density（MOD） image was analyzed by Image Pro Plusversion（IPP） image processing software. Result:Serum melatonin concentration in patients with PTC was significantly higher than that in MNG patients and normal controls（P<0.05）. The level of melatonin in the primary tumor T≥2 cm group was significantly higher than that in the T<2 cm group. Patients with positive cervical lymph nodes（N≥1） had significantly higher melatonin levels than lymph node negatives（N=0）（P<0.05）. The MT1 and MT2 receptors were expressed in both PTC and paracancerous tissues, mainly in the cell membrane and cytoplasm. The expression of MT1 receptor was low in the two groups, and there was no statistical difference. The expression of MT2 receptor in PTC tissues Significantly higher than the adjacent tissues（P<0.05）, further studies showed that the expression of MT2 receptor in PTC tissues was associated with cervical lymph node metastasis, and the expression of MT2 receptor in PTC tissues with cervical lymph node metastasis was significantly lower than that without metastasis （P<0.05）. Conclusion:Serum melatonin levels in PTC patients were higher than those in MNG and control groups, which may be associated with low malignancy of PTC; melatonin inhibits PTC metastasis, which exerts anti-PTC metastasis mainly through MT2 receptors.

Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.

KEYWORDS:
lymphatic metastasis; melatonin; melatonin receptor; papillary thyroid cancer

PMID:

31914295

DOI:

10.13201/j.issn.1001-1781.2019.11.013

 

[S.Seneff]

Cellular and Molecular Life Sciences

https://doi.org/10.1007/s00018-019-03438-1

REVIEW

Melatonin inhibits Warburg‑dependent cancer by redirecting glucose
oxidation to the mitochondria: a mechanistic hypothesis

Russel J. Reiter1 · Ramaswamy Sharma1

· Qiang Ma1
· Sergio Rorsales‑Corral2
· Luiz G. de Almeida Chufa3
Received: 3 October 2019 / Revised: 16 December 2019 / Accepted: 23 December 2019
© Springer Nature Switzerland AG 2020
Abstract

Melatonin has the ability to intervene in the initiation, progression and metastasis of some experimental cancers. A large vari-
ety of potential mechanisms have been advanced to describe the metabolic and molecular events associated with melatonin’s
interactions with cancer cells. There is one metabolic perturbation that is common to a large number of solid tumors and
accounts for the ability of cancer cells to actively proliferate, avoid apoptosis, and readily metastasize, i.e., they use cytosolic
aerobic glycolysis (the Warburg efect) to rapidly generate the necessary ATP required for the high metabolic demands of
the cancer cells. There are several drugs, referred to as glycolytic agents, that cause cancer cells to abandon aerobic glyco-
lysis and shift to the more conventional mitochondrial oxidative phosphorylation for ATP synthesis as in normal cells. In
doing so, glycolytic agents also inhibit cancer growth. Herein, we hypothesize that melatonin also functions as an inhibi-
tor of cytosolic glycolysis in cancer cells using mechanisms, i.e., downregulation of the enzyme (pyruvate dehydrogenase
kinase) that interferes with the conversion of pyruvate to acetyl CoA in the mitochondria, as do other glycolytic drugs. In
doing so, melatonin halts the proliferative activity of cancer cells, reduces their metastatic potential and causes them to more
readily undergo apoptosis. This hypothesis is discussed in relation to the previously published reports. Whereas melatonin
is synthesized in the mitochondria of normal cells, we hypothesize that this synthetic capability is not present in cancer
cell mitochondria because of the depressed acetyl CoA; acetyl CoA is necessary for the rate limiting enzyme in melatonin
synthesis, arylalkylamine-N-acetyltransferase. Finally, the ability of melatonin to switch glucose oxidation from the cytosol
to the mitochondria also explains how tumors that become resistant to conventional chemotherapies are re-sensitized to the
same treatment when melatonin is applied.

Keywords Pyruvate dehydrogenase kinase · Pyruvate dehydrogenase complex · Chemosensitivity · Glycolysis · Acetyl
CoA · Citric acid cycle · Dichloroacetate · Glycolytics

Conclusions and perspectives

This review provides a novel perspective on how melatonin
interferes with cancer cell metabolism, growth, and metas-
tasis (Fig. 2). This cancer-inhibiting mechanism, in addi-
tion to other processes identifed in earlier studies, makes it
important to further test melatonin as an oncostatic agent at
the clinical level. This is of special importance since can-
cer patients more frequently die from metastatic than from
non-metastatic cancer (Fig. 5). Considering that melatonin
controls tumor growth and limits their size (large tumors
more readily metastasize) as well as to its direct anti-meta-
static actions more than justifes tests of its efcacy....