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TRIM46 deficiency‑induced DNA damage enhances the sensitivity of cisplatin in non‑small cell lung cancer by regulating the Akt signaling pathway

  • Authors:
    • Song Jin
    • Dandan Zhang
    • Zhicheng Liao
    • Lingpei Yu
    • Yuanyuan Wang
    • Pengcheng Jia
    • Minmin Pan
    • Yifan Li
    • Jizhou Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Oncology, Wenzhou Traditional Chinese Medicine Hospital of Zhejiang Chinese Medical University, Wenzhou, Zhejiang 325000, P.R. China, Traditional Chinese Medicine Research and Experimental Center, Wenzhou Traditional Chinese Medicine Hospital of Zhejiang Chinese Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Encephalopathy, Rui'an Traditional Chinese Medicine Hospital, Wenzhou, Zhejiang 325000, P.R. China, Department of Gastroenterology, Yueqing Traditional Chinese Medicine Hospital, Yueqing, Zhejiang 325600, P.R. China
    Copyright: © Jin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 58
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    Published online on: January 28, 2026
       https://doi.org/10.3892/or.2026.9063
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Abstract

Lung cancer is one of the most aggressive malignancies worldwide. Non‑small cell lung cancer (NSCLC), in particular, is characterized by a poor 5‑year survival rate, which is largely attributable to cisplatin (DDP) resistance. However, the molecular mechanisms underlying DDP resistance are still not fully understood. Tripartite motif 46 (TRIM46) is implicated in promoting the progression of lung adenocarcinoma and enhancing chemoresistance. Nevertheless, its specific role in DDP resistance remains elusive. The present study aimed to investigate the role of TRIM46 in DDP resistance. Immunohistochemistry and TUNEL staining were employed to detect the expression of TRIM46 and apoptotic cells in tumor tissues. Lentiviruses were used to construct TRIM46 overexpression and knockdown vectors in A549 and A549/DDP cells. Cell proliferation, apoptosis and DNA damage were measured by Cell Counting Kit‑8, flow cytometry and comet assay, respectively. Subcutaneous implantation model through injection of A549/DDP cells with TRIM46 knockdown was performed in BALB/c nude female mice, followed by DDP treatment. The results revealed that TRIM46 was highly expressed in DDP‑resistant NSCLC tumor tissues and positively associated with DDP resistance. TRIM46 overexpression attenuated the DDP‑induced apoptosis and DNA damage of A549 cells. Meanwhile, the knockdown of TRIM46 enhanced the DDP‑induced apoptosis and DNA damage in A549/DDP cells. Mechanistically, TRIM46 activated the Akt signaling, thus inhibiting the expression of caspase 3 and cleaved‑caspase 3 as well as increasing the expression level of DNA repair protein RAD51. Furthermore, TRIM46 deficiency inhibited tumor growth and increased DDP sensitivity in vivo. In conclusion, the results of the present study demonstrated that TRIM46 contributed to DDP resistance by regulating the Akt signaling pathway and DNA damage, thereby offering new strategies for lung cancer therapy.
View Figures

Figure 1

TRIM46 expression is associated with
DDP resistance in non-small cell lung cancer tissues. (A)
Immunohistochemistry staining was performed using a TRIM46 antibody
and normal, DDP-sensitive and DDP-resistant tissues. (B)
Percentages of tissues with low or high TRIM46 expression in
DDP-sensitive (n=38) or DDP-resistant (n=47) patients. (C)
Percentages of patients with DDP-resistant or DDP-sensitive tissues
and low (n=44) or high (n=41) TRIM46 expression. ***P<0.001.
TRIM46, tripartite motif 46; DDP, cisplatin.

Figure 2

TRIM46 upregulation contributes to
DDP resistance in non-small cell lung cancer cells. (A) RT-qPCR
(left) and western blot (right) analysis of TRIM46 expression in
16HBE, A549 and A549/DDP cells. (B) RT-qPCR (left) and western blot
(right) analysis of TRIM46 expression in A549 cells infected with
TRIM46 overexpression lentivirus. (C) Cell apoptosis was measured
after transduction with TRIM46-overexpression lentivirus and/or DDP
treatment (0, 5 and 10 µM) in A549 cells. (D) Quantitative analysis
of cell apoptosis. (E) Representative images of the comet assay
showing DNA fragmentation after transduction with
TRIM46-overexpression lentivirus and/or DDP treatment (0, 5 and 10
µM) in A549 cells (scale bar, 50 µm; magnification, ×400). (F)
Quantification of tail DNA (%) revealing DNA damage after
transduction with TRIM46-overexpression lentivirus and/or DDP
treatment (0, 5 and 10 µM) in A549 cells. *P<0.05, **P<0.01,
***P<0.001. TRIM46, tripartite motif 46; DDP, cisplatin;
RT-qPCR, reverse transcription-quantitative polymerase chain
reaction; PI, propidium iodide.

Figure 3

TRIM46 knockdown alleviates DDP
resistance in non-small cell lung cancer cells. (A) Reverse
transcription-quantitative polymerase chain reaction (left) and
western blot (right) analysis of TRIM46 expression in A549/DPP
cells infected with TRIM46 knockdown lentiviruses. (B) Cell
apoptosis was measured after transduction with TRIM46 knockdown
lentivirus and/or DDP treatment (0, 50 and 100 µM) in A549/DDP
cells. (C) Quantitative analysis of cell apoptosis. (D)
Representative images of the comet assay showing DNA fragmentation
after transduction with TRIM46 knockdown lentivirus and/or DDP
treatment (0, 50 and 100 µM) in A549/DDP cells (scale bar, 50 µm;
magnification, ×400). (E) Quantification of tail DNA (%) revealing
DNA damage after transduction with TRIM46 knockdown lentivirus
and/or DDP treatment (0, 50 and 100 µM) in A549/DDP cells.
***P<0.001. TRIM46, tripartite motif 46; DDP, cisplatin; sh,
short hairpin; NC, negative control; PI, propidium iodide.

Figure 4

TRIM46 depletion inhibits cell
proliferation by regulating the Akt signaling pathway. (A) Cell
proliferation of A549/DDP cells transduced with TRIM46-knockdown
lentiviruses. (B) Western blot analysis of p-Akt, Akt, caspase 3,
cleaved-caspase 3 and RAD51 expression in A549/DDP cells transduced
with TRIM46-knockdown lentiviruses. (C) Cell proliferation of A549
cells transduced with TRIM46-overexpression lentivirus and/or
treated with LY294002 (20 µM) or vehicle. (D) Western blot analysis
of p-Akt, Akt, caspase 3, cleaved-caspase 3 and RAD51 in A549 cells
transduced with TRIM46-overexpression lentivirus and/or treated
with LY294002 (20 µM) or vehicle. ***P<0.001 vs. shNC or Vector
+ Vehicle; ###P<0.001 vs. TRIM46 + Vehicle. TRIM46,
tripartite motif 46; DDP, cisplatin; sh, short hairpin; NC,
negative control; OD, optical density; p-, phosphorylated.

Figure 5

TRIM46 knockdown increases the
sensitivity of xenograft tumors to DDP treatment. (A) Tumor volumes
and (B) images of xenograft tumors in the designated groups (scale
bar, 1 cm; n=6 per group). (C) TUNEL assay of xenograft tumor
samples (scale bar, 100 µm; magnification, ×200). (D) Statistical
analysis of the TUNEL assay (n=6 per group). (E) Western blot
analysis of TRIM46 and RAD51 expression in xenograft tumors.
***P<0.001. TRIM46, tripartite motif 46; DDP, cisplatin; sh,
short hairpin; NC, negative control.

Figure 6

Mechanism of TRIM46
deficiency-induced DNA damage, enhancing the sensitivity of DDP in
NSCLC by regulating Akt signaling pathway. (A) TRIM46 expression
was positively associated with DDP resistance in NSCLC tissues. (B)
TRIM46 overexpression significantly suppressed DDP-induced
apoptosis and enhanced DDP resistance in A549 cells. (C) TRIM46
knockdown induced DNA damage by modulating the protein levels of
p-AKT, RAD51, caspase 3, and cleaved-caspase 3, thereby resulting
in cell proliferation inhibition in NSCLC cells. (D) TRIM46
knockdown increased the sensitivity of xenograft tumors to DDP
treatment. NSCLC, non-small cell lung cancer; TRIM46, tripartite
motif 46; DDP, cisplatin; p-, phosphorylated.
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Spandidos Publications style
Jin S, Zhang D, Liao Z, Yu L, Wang Y, Jia P, Pan M, Li Y and Zhang J: TRIM46 deficiency‑induced DNA damage enhances the sensitivity of cisplatin in non‑small cell lung cancer by regulating the Akt signaling pathway. Oncol Rep 55: 58, 2026.
APA
Jin, S., Zhang, D., Liao, Z., Yu, L., Wang, Y., Jia, P. ... Zhang, J. (2026). TRIM46 deficiency‑induced DNA damage enhances the sensitivity of cisplatin in non‑small cell lung cancer by regulating the Akt signaling pathway. Oncology Reports, 55, 58. https://doi.org/10.3892/or.2026.9063
MLA
Jin, S., Zhang, D., Liao, Z., Yu, L., Wang, Y., Jia, P., Pan, M., Li, Y., Zhang, J."TRIM46 deficiency‑induced DNA damage enhances the sensitivity of cisplatin in non‑small cell lung cancer by regulating the Akt signaling pathway". Oncology Reports 55.4 (2026): 58.
Chicago
Jin, S., Zhang, D., Liao, Z., Yu, L., Wang, Y., Jia, P., Pan, M., Li, Y., Zhang, J."TRIM46 deficiency‑induced DNA damage enhances the sensitivity of cisplatin in non‑small cell lung cancer by regulating the Akt signaling pathway". Oncology Reports 55, no. 4 (2026): 58. https://doi.org/10.3892/or.2026.9063
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Spandidos Publications style
Jin S, Zhang D, Liao Z, Yu L, Wang Y, Jia P, Pan M, Li Y and Zhang J: TRIM46 deficiency‑induced DNA damage enhances the sensitivity of cisplatin in non‑small cell lung cancer by regulating the Akt signaling pathway. Oncol Rep 55: 58, 2026.
APA
Jin, S., Zhang, D., Liao, Z., Yu, L., Wang, Y., Jia, P. ... Zhang, J. (2026). TRIM46 deficiency‑induced DNA damage enhances the sensitivity of cisplatin in non‑small cell lung cancer by regulating the Akt signaling pathway. Oncology Reports, 55, 58. https://doi.org/10.3892/or.2026.9063
MLA
Jin, S., Zhang, D., Liao, Z., Yu, L., Wang, Y., Jia, P., Pan, M., Li, Y., Zhang, J."TRIM46 deficiency‑induced DNA damage enhances the sensitivity of cisplatin in non‑small cell lung cancer by regulating the Akt signaling pathway". Oncology Reports 55.4 (2026): 58.
Chicago
Jin, S., Zhang, D., Liao, Z., Yu, L., Wang, Y., Jia, P., Pan, M., Li, Y., Zhang, J."TRIM46 deficiency‑induced DNA damage enhances the sensitivity of cisplatin in non‑small cell lung cancer by regulating the Akt signaling pathway". Oncology Reports 55, no. 4 (2026): 58. https://doi.org/10.3892/or.2026.9063
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