Methionine restriction inhibits pancreatic cancer proliferation while suppressing JAK2/STAT3 pathway

Manabu Maebashi1, Kentaro Miyake1, Jun Yamamoto1

  • 1Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Abstract

Insights

Methionine restriction (MR) inhibits pancreatic cancer (PC) growth by suppressing the JAK2/STAT3 pathway and decreasing NF-kB. This study reveals MR’s anti-tumor mechanism in PC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Nutritional Science

Background:

  • Methionine restriction (MR) shows anti-tumor effects in various cancers, including pancreatic cancer (PC).
  • The precise molecular mechanisms underlying MR's anti-cancer activity in PC are not fully understood.
  • Proteomic analysis is employed to elucidate MR's impact on PC.

Purpose of the Study:

  • To investigate the underlying molecular mechanisms of methionine restriction (MR) in pancreatic cancer (PC).
  • To identify key proteins and pathways affected by MR in PC cell lines and in vivo models.

Main Methods:

  • Human PC cell lines were cultured under standard and MR conditions.
  • Proteomic analysis and Ingenuity Pathway Analysis (IPA) were used to identify differentially expressed proteins.
  • Validation was performed using western blotting, real-time PCR, ELISA, and immunohistochemistry in an in vivo mouse model.

Main Results:

  • MR significantly suppressed pancreatic cancer cell proliferation in vitro.
  • Proteomic and validation studies revealed decreased expression of STAT3 and NF-kB in MR-treated cells.
  • In vivo studies demonstrated a significant reduction in tumor volume and suppressed STAT3 expression in the MR group.

Conclusions:

  • Methionine restriction effectively suppresses pancreatic cancer growth.
  • The JAK2/STAT3 signaling pathway and NF-kB are key targets of MR in pancreatic cancer.

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.7K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
8.7K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.4K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.4K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.2K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.7K