Sunitinib and Pterostilbene Combination Treatment Exerts Antitumor Effects in Gastric Cancer via Suppression of PDZD8
Abstract
:1. Introduction
2. Results
2.1. Effect of SUN and PTE on Gastric Cancer Cells
2.2. Effect of SUN on Mitochondrial Function
2.3. Role of PDZD8 in Gastric Cancer Cells
2.4. Effects of SUN Treatment or PDZD8 Knockdown on Mitochondrial Respiration
2.5. Effect of Extrinsic PDZD Protein on SUN and PTE-Induced Cell Growth Inhibition in TMK1 Cells
2.6. Effect of SUN and PTE on Mouse Tumors
3. Discussion
4. Materials and Methods
4.1. Cell Lines and Reagents
4.2. Cell Growth and Apoptosis
4.3. Mitochondrial Imaging
4.4. mRNA Profiling
4.5. Extracellular Flux Analysis
4.6. Protein Extraction
4.7. Immunoblot Analysis
4.8. Immunoprecipitation
4.9. Tissue Microarray and Surgical Specimens
4.10. Small Interfering RNA
4.11. Enzyme-Linked Immunosorbent Assay (ELISA)
4.12. Extrinsic PDZD8 Protein Administration
4.13. RT-PCR
4.14. Animals
4.15. Animal Tumor Models
4.16. Immunohistochemistry
4.17. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
SUN | sunitinib |
PTE | pterostilbene |
TKI | tyrosine kinase inhibitor |
ER | endoplasmic reticulum |
MAM | Mitochondria-associated endoplasmic reticulum membrane |
PDZD8 | PDZ domain-containing protein 8 |
MMP | mitochondrial membrane potential |
OCR | oxygen consumption rate |
LETM1 | leucine zipper and EF-hand containing transmembrane protein 1 |
QFM | quadriceps femoris muscle |
VDAC1 | voltage-dependent anion channel 1 |
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Gene Symbol | MKN74 | TMK1 | Gene Symbol | MKN74 | TMK1 |
---|---|---|---|---|---|
PCNA | −2.91 | −5.16 | GPT | 1.18 | 1.15 |
SLC38A5 | −1.53 | −11.7 | LDHD | 1.21 | 1.11 |
TGM2 | −1.38 | −58.84 | SLC16A13 | 1.24 | 1.11 |
ME2 | −2.57 | −2.33 | ACO1 | 1.29 | 1.24 |
CKLF | −1.64 | −4.35 | GAD1 | 1.12 | 1.43 |
L2HGDH | −2.59 | −1.93 | ME3 | 1.88 | 1.2 |
PDHA1 | −2.58 | −1.57 | ACO2 | 1.18 | 1.91 |
PFKP | −2.34 | −1.78 | SLC16A5 | 1.53 | 1.58 |
CKB | −1.39 | −2.81 | SLC38A10 | 1.55 | 1.59 |
PDK1 | −1.12 | −2.82 | PDK2 | 1.72 | 1.82 |
SLC38A4 | −2.18 | −1.21 | SLC38A9 | 2.19 | 1.49 |
GAD2 | −1.13 | −2.11 | SLC38A2 | 2.34 | 1.46 |
TGM1 | −1.65 | −1.63 | PDP1 | 2.88 | 1.12 |
LDHB | −1.66 | −1.26 | GLS | 4.35 | 1.11 |
SLC16A3 | −1.15 | −1.66 | ME1 | 2.17 | 1.69 |
GPT2 | −1.38 | −1.59 | SLC17A5 | 1.65 | 3.09 |
GOT2 | −1.56 | −1.1 | SLC16A4 | 3.63 | 2.17 |
OGFOD1 | −1.18 | −1.52 | PDK4 | 1.74 | 5.81 |
PKM | −1.31 | −1.5 | |||
PDHX | −1.48 | −1.21 | |||
OGDHL | −1.17 | −1.31 | |||
CKM | −1.29 | −1.15 | |||
PFKL | −1.11 | −1.22 |
Gene Symbol | MKN74 | TMK1 | Gene Symbol | MKN74 | TMK1 |
---|---|---|---|---|---|
IRF2BPL | −3.27 | −2.66 | ZNF474 | 2.13 | 1.03 |
IRF2BP2 | −2.59 | −2 | MSS51 | 2.07 | 1.51 |
PLEKHM3 | −2.47 | −2.77 | ZNF608 | 1.91 | 1.43 |
PLEKHM1 | −2.25 | −2.33 | ENPP4 | 1.86 | −1.13 |
TIMM10B | −2.01 | −2.05 | SNRNP48 | 1.84 | 1.74 |
ZNF428 | −1.98 | 1.05 | ITGAE | 1.84 | 1.73 |
LENG9 | −1.79 | −1.29 | FREM3 | 1.65 | 1.28 |
ASPHD2 | −1.79 | −1.09 | PDE6A | 1.65 | 1.16 |
AMDHD1 | −1.64 | −1.55 | TOPAZ1 | 1.61 | 1.18 |
ZNF609 | −1.56 | −1.22 | SLC39A5 | 1.61 | 1.18 |
PDZD8 | −1.45 | −1.38 | SLC39A8 | 1.57 | 1.63 |
MOB2 | −1.44 | −1.56 | FRAS1 | 1.51 | −1.27 |
Parameter | n | PDZD8 Expression | High | p Value (1) | ||
---|---|---|---|---|---|---|
Low | Moderate | |||||
Total | 85 | 8 | 39 | 38 | ||
Age | 32–62 yrs (4) | 42 | 4 | 18 | 20 | NS (2) |
63–90 yrs | 43 | 4 | 21 | 18 | ||
Sex | Male | 68 | 5 | 31 | 32 | NS |
Female | 17 | 3 | 8 | 6 | ||
pT (3) | 1 | 10 | 3 | 5 | 2 | 0.031 |
2 | 25 | 4 | 12 | 9 | ||
3 | 44 | 1 | 21 | 22 | ||
4 | 6 | 0 | 1 | 5 | ||
pN (3) | 0 | 65 | 8 | 31 | 26 | NS |
1–2 | 20 | 0 | 8 | 12 | ||
pStage (3) | 1 | 34 | 7 | 16 | 11 | 0.0106 |
2 | 44 | 1 | 22 | 21 | ||
3–4 | 7 | 0 | 1 | 6 | ||
Grade (3) | 1 | 14 | 3 | 5 | 6 | NS |
2 | 24 | 1 | 11 | 12 | ||
3 | 47 | 4 | 23 | 20 |
Tissue | n | PDZD8 Expression | Moderate | High | p Value (1) | |
---|---|---|---|---|---|---|
Negative | Low | |||||
Foveolar epithelium | 35 | 35 | 0 | 0 | 0 | |
Pyloric gland | 24 | 24 | 0 | 0 | 0 | |
Fundic gland | 11 | 11 | 0 | 0 | 0 | |
Intestinal metaplasia | 12 | 12 | 0 | 0 | 0 | |
Adenoma | 11 | 11 | 0 | 0 | 0 | |
Adenocarcinoma | 85 | 0 | 8 | 39 | 38 | <0.0001 |
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Hojo, Y.; Kishi, S.; Mori, S.; Fujiwara-Tani, R.; Sasaki, T.; Fujii, K.; Nishiguchi, Y.; Nakashima, C.; Luo, Y.; Shinohara, H.; et al. Sunitinib and Pterostilbene Combination Treatment Exerts Antitumor Effects in Gastric Cancer via Suppression of PDZD8. Int. J. Mol. Sci. 2022, 23, 4002. https://doi.org/10.3390/ijms23074002
Hojo Y, Kishi S, Mori S, Fujiwara-Tani R, Sasaki T, Fujii K, Nishiguchi Y, Nakashima C, Luo Y, Shinohara H, et al. Sunitinib and Pterostilbene Combination Treatment Exerts Antitumor Effects in Gastric Cancer via Suppression of PDZD8. International Journal of Molecular Sciences. 2022; 23(7):4002. https://doi.org/10.3390/ijms23074002
Chicago/Turabian StyleHojo, Yudai, Shingo Kishi, Shiori Mori, Rina Fujiwara-Tani, Takamitsu Sasaki, Kiyomu Fujii, Yukiko Nishiguchi, Chie Nakashima, Yi Luo, Hisashi Shinohara, and et al. 2022. "Sunitinib and Pterostilbene Combination Treatment Exerts Antitumor Effects in Gastric Cancer via Suppression of PDZD8" International Journal of Molecular Sciences 23, no. 7: 4002. https://doi.org/10.3390/ijms23074002