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Effects of sesamin on the chemosensitivity, invasiveness and immune evasion mechanism of human lung adenocarcinoma

  • Authors:
    • Chia-Chia Chao
    • Pei-Wen Peng
    • Yen-You Lin
    • An-Chen Chang
  • View Affiliations / Copyright

    Affiliations: Department of Respiratory Therapy, Fu Jen Catholic University, New Taipei City 242062, Taiwan, R.O.C., School of Dental Technology, Taipei Medical University, Taipei 110301, Taiwan, R.O.C., Translational Medicine Center, Research Department, Shin Kong Wu Ho‑Su Memorial Hospital, Taipei 111045, Taiwan, R.O.C.
    Copyright: © Chao et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 4.0].
  • Article Number: 194
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    Published online on: September 11, 2025
       https://doi.org/10.3892/ijmm.2025.5635
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Abstract

Lung adenocarcinoma (LUAD) is a major cause of cancer‑related mortality worldwide. Sesamin is a lignan with potent anticancer properties and promising therapeutic potential. In the present study, it was aimed to investigate the specific mechanisms through which sesamin reduces cell invasiveness and cancer‑associated immunosuppression in LUAD cells. The effects of sesamin on LUAD cell invasiveness were investigated using a wound healing assay and anoikis resistance assay. NK‑92 MI cells were used to analyze cancer‑associated immunosuppression upon sesamin treatment. The therapeutic effect of sesamin in LUAD was measured using a subcutaneous mouse model. Our results indicated that sesamin inhibited the proliferation, survival and migration of LUAD cells (A549 and CL1‑5) in a dose‑dependent manner. Sesamin also enhanced the proapoptotic effects of chemotherapeutic agents such as docetaxel and paclitaxel through the activation of the caspase‑3/poly(ADP‑ribose) polymerase pathway. In addition, sesamin reduced cancer cell migration and anoikis resistance by downregulating the expression of N‑cadherin and inhibiting the phosphoinositide 3‑kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. It also induced the downregulation of programmed death ligand 1 through hsa‑microRNA‑34a‑5p, resulting in the increased cytotoxicity of natural killer cells. This sequence of events consequently interfered with the immune evasion mechanism of LUAD cells. In conclusion, sesamin has a multifaceted effect on the migration, anoikis resistance and antitumor immunity of LUAD cells, indicating its potential as adjunctive therapy.
View Figures

Figure 1

Sesamin reduces the viability of
human LUAD cells in a dose-dependent manner. (A-D) The effect of
various concentrations of sesamin (0-100 μM) on the
viability and survival of LUAD cells was evaluated using MTT and
colony formation assays, respectively. (E and F) LUAD cells were
treated with sesamin at a concentration of 100 μM, and cell
proliferation was evaluated using Ki-67 staining. Scale bars, 100
μm. Data are expressed as mean ± SD for triplicate samples.
*P<0.05, **P<0.01,
***P<0.001 and ****P<0.0001 relative to
the control group. LUAD, lung adenocarcinoma; ns, not
significant.

Figure 2

Sesamin increases the
chemosensitivity of LUAD cells. (A-F) Viability and survival of
LUAD cells treated with sesamin in combination with a
chemotherapeutic agent (12.5 μM docetaxel or 5 μM
paclitaxel), evaluated using both an MTT assay after incubation for
24 h and a colony formation assay after incubation for 1 week. (G
and H) The protein expression levels of cleaved caspase-3 and PARP
in LUAD cells were determined using a western blot assay after
treatment with sesamin in combination with a chemotherapeutic agent
(docetaxel or paclitaxel). Data are expressed as the mean ± SD for
triplicate samples. *P<0.05, **P<0.01,
***P<0.001 and ****P<0.0001 relative to
the control group. LUAD, lung adenocarcinoma; PARP,
poly(ADP-ribose) polymerase.

Figure 3

Sesamin reduces the motility and
anoikis resistance of LUAD cells by downregulating N-cadherin. (A
and B) The expression levels of epithelial to mesenchymal
transition-related markers, including E-cadherin, vimentin and
N-cadherin, were determined using a western blot assay in lung
adenocarcinoma cells treated with various concentrations of sesamin
(0-100 μM). (C and D) Cell motility determined using a wound
healing assay after 24 h of treatment with sesamin. Scale bars, 100
μm. (E) A549 cells treated with sesamin (0-50 μM) for
2, 4 and 6 days, with an anoikis resistance assay by measuring cell
numbers. Scale bars, 250 μm. Data are expressed as the mean
± SD for triplicate samples. *P<0.05,
**P<0.01, ***P<0.001 and
****P<0.0001 relative to the control group. ns, not
significant.

Figure 4

Sesamin reduces the motility and
anoikis resistance of LUAD cells by downregulating PI3K/AKT/mTOR.
(A and B) The protein expression levels of p-PI3K, p-AKT, and
p-mTOR in LUAD cells were determined using a western blot assay
after treatment with sesamin (100 μM) at various time
points. (C-F) Pretreatment of LUAD cells with activators of PI3K
(740 Y-P, 1 mM), AKT (SC79, 0.5 μg/ml) and mTOR (MHY1485, 1
mM) for 30 min was followed by treatment with sesamin (100
μM) for 2 h. The protein levels of AKT and mTOR
phosphorylation were detected using a western blot assay. (G-L)
Pretreatment of LUAD cells with activators of PI3K (740 Y-P, 1 mM),
AKT (SC79, 0.5 μg/ml), and mTOR (MHY1485, 1 mM) for 30 min,
followed by treatment with sesamin (100 μM) for 24 h. The
protein levels of N-cadherin were determined by western blot assay.
(M-O) Cell migration and anoikis resistance were determined using
wound healing and anoikis resistance assays, respectively. Scale
bars, 100 μm (wound healing) and 250 μm (anoikis
resistance). Data are expressed as the mean ± SD for triplicate
samples. *P<0.05, **P<0.01,
***P<0.001 and ****P<0.0001 relative to
the control group. LUAD, lung adenocarcinoma; p-,
phosphorylated.

Figure 5

Sesamin downregulates the expression
of PD-L1 and mitigates cancer-associated immunosuppression. (A and
B) The protein expression of PD-L1 in LUAD cells treated with
various concentrations of sesamin (0-100 μM) was determined
using a western blot assay. (C and D) LUAD cells were stained with
calcein AM (a green fluorescent marker) after a 24-h sesamin
treatment (100 μM). Following the introduction of NK cells,
cytotoxicity was quantitatively evaluated by measuring the
fluorescence values. Scale bars, 200 μm. Data are expressed
as the mean ± SD for triplicate samples. *P<0.05,
**P<0.01 and ****P<0.0001 relative to
the control group. PD-L1, programmed death ligand 1; LUAD, lung
adenocarcinoma; NK cells, natural killer cells; ns, not
significant.

Figure 6

Hsa-miR-34a mediates the
sesamin-induced downregulation of PD-L1 and enhances the
cytotoxicity of NK cells. (A and B) The expression of
hsa-miR-34a-5p in LUAD cells, treated with various concentrations
of sesamin (0-100 μM), was determined using a reverse
transcription-quantitative PCR assay. (C and D) LUAD cells
transfected with either a control inhibitor or hsa-miR-34a-5p
inhibitor (25 nM) for 24 h, followed by treatment with sesamin (100
μM) for another 24 h. The protein levels of PD-L1 were
detected using a western blot assay. (E) Schematic representation
of the 3′-UTR of the WT PD-L1 sequence and the mutant PD-L1
sequence containing the miR-34a binding site. (F and G) LUAD cells
were co-transfected with a PD-L1 plasmid (1 μg/μl)
and a miR-34a inhibitor (25 nM) for 24 h, followed by stimulation
with sesamin for an additional 24 h. Relative luciferase and
Renilla activities were then measured. (H) NK cytotoxicity assay
revealing the immune evasion of CL1-5 cells transfected with a
hsa-miR-34a-5p inhibitor (25 nM) for 24 h, followed by treatment
with sesamin (100 μM). (I and J) LUAD cells were transfected
with either a control mimic or hsa-miR-34a-5p mimic (25 nM) for 24
h, and PD-L1 protein expression was measured using a western blot
assay. (K) Immune evasion was assessed through a NK cytotoxicity
assay after transfecting CL1-5 cells with a hsa-miR-34a-5p mimic
(25 nM) for 24 h. Data are expressed as the mean ± SD for
triplicate samples. *P<0.05, **P<0.01,
***P<0.001 and ****P<0.0001 relative to
the control group.. PD-L1, programmed death ligand 1; NK cells;
natural killer cells; miR, microRNA; LUAD, lung adenocarcinoma;
UTR, untranslated region; WT, wild-type; ns, not significant.

Figure 7

Sesamin inhibits lung tumor growth
in vivo. (A) Flowchart demonstrating the protocol for
sesamin treatment with a subcutaneous animal model. (B)
Representative images of tumors excised from each group were
obtained after 4 weeks of sesamin treatment. (C) Tumor weights of
the treatment and control groups. (D) Expression of N-cadherin and
PD-L1 proteins in tumor tissues, determined using an IHC analysis.
(E) Quantitative IHC analysis of N-cadherin and PD-L1 expression.
Data are expressed as the mean ± SD for triplicate samples.
*P<0.05 relative to the control group. PD-L1,
programmed death ligand 1; IHC, immunohistochemical.

Figure 8

Graphical representation of the
mechanisms underlying the effect of sesamin on LUAD cells. Sesamin
inhibits cancer cell motility and anoikis resistance primarily
through the suppression of EMT. Sesamin also enhances antitumor
immunity by downregulating the expression of PD-L1, thereby
confirming the tumor-suppressive effects of sesamin in human LUAD.
LUAD, lung adenocarcinoma; EMT, epithelial-mesenchymal transition;
PD-L1, programmed death ligand 1.
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Copy and paste a formatted citation
Spandidos Publications style
Chao C, Peng P, Lin Y and Chang A: Effects of sesamin on the chemosensitivity, invasiveness and immune evasion mechanism of human lung adenocarcinoma. Int J Mol Med 56: 194, 2025.
APA
Chao, C., Peng, P., Lin, Y., & Chang, A. (2025). Effects of sesamin on the chemosensitivity, invasiveness and immune evasion mechanism of human lung adenocarcinoma. International Journal of Molecular Medicine, 56, 194. https://doi.org/10.3892/ijmm.2025.5635
MLA
Chao, C., Peng, P., Lin, Y., Chang, A."Effects of sesamin on the chemosensitivity, invasiveness and immune evasion mechanism of human lung adenocarcinoma". International Journal of Molecular Medicine 56.5 (2025): 194.
Chicago
Chao, C., Peng, P., Lin, Y., Chang, A."Effects of sesamin on the chemosensitivity, invasiveness and immune evasion mechanism of human lung adenocarcinoma". International Journal of Molecular Medicine 56, no. 5 (2025): 194. https://doi.org/10.3892/ijmm.2025.5635
Copy and paste a formatted citation
x
Spandidos Publications style
Chao C, Peng P, Lin Y and Chang A: Effects of sesamin on the chemosensitivity, invasiveness and immune evasion mechanism of human lung adenocarcinoma. Int J Mol Med 56: 194, 2025.
APA
Chao, C., Peng, P., Lin, Y., & Chang, A. (2025). Effects of sesamin on the chemosensitivity, invasiveness and immune evasion mechanism of human lung adenocarcinoma. International Journal of Molecular Medicine, 56, 194. https://doi.org/10.3892/ijmm.2025.5635
MLA
Chao, C., Peng, P., Lin, Y., Chang, A."Effects of sesamin on the chemosensitivity, invasiveness and immune evasion mechanism of human lung adenocarcinoma". International Journal of Molecular Medicine 56.5 (2025): 194.
Chicago
Chao, C., Peng, P., Lin, Y., Chang, A."Effects of sesamin on the chemosensitivity, invasiveness and immune evasion mechanism of human lung adenocarcinoma". International Journal of Molecular Medicine 56, no. 5 (2025): 194. https://doi.org/10.3892/ijmm.2025.5635
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