TPX2 knockdown mediates p53 activation to induce autophagy and apoptosis for anti-colorectal cancer effects
Yunfei Dong1, Guixian Sheng2, Wenbin Chen2
1Department of Anorectal, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China.
Abstract:
Colorectal cancer (CRC) exhibits high morbidity and mortality worldwide. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) impacts various cancers; however, mechanism of TPX2 in CRC remains unclear. Xenograft nude mouse models were constructed by subcutaneous injection of HCT116 cells with sh-NC, sh-TPX2, OE-NC, and OE-TPX2 transfection. Following the test of tumor growth, immunohistochemistry and TUNEL staining were done. In vitro, HCT116, RKO, and SW480 cells were divided into sh-NC, sh-TPX2, and sh-TPX2 + 3-methyladenine (3-MA, autophagy inhibitor) groups. Further, sh-p53 and rapamycin (RA, autophagy agonist) were added in HCT116 cells. EdU staining, flow cytometry, transparent electron microscopy, and Western blot were performed. Comparing with sh-NC group, sh-TPX2 inhibited tumor growth and Ki67 expression, and increased LC3-II expression and apoptosis, whereas OE-TPX2 group presented an opposite trend. In vitro, HCT116 and RKO cells in sh-TPX2 group enhanced apoptosis and LC3 II/LC3 I expression, and inhibited proliferation and P62 expression, which were reversed after further 3-MA intervention. The above results were not found in SW480 cells. Moreover, compared to sh-TPX2 group, sh-TPX2 + RA group enhanced apoptosis and autophagy, and suppressed the proliferation of HCT116 cells, which were reversed following further sh-p53 intervention. Therefore, sh-TPX2 mediated p53 activation to induce autophagy for anti-CRC effects, providing new ideas for CRC treatment.
Insights
Targeting protein for Xenopus kinesin-like protein 2 (TPX2) inhibits colorectal cancer (CRC) growth by activating p53 to induce autophagy. This study reveals TPX2 as a potential therapeutic target for CRC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Colorectal cancer (CRC) presents a significant global health challenge with high morbidity and mortality.
- The role of Targeting protein for Xenopus kinesin-like protein 2 (TPX2) in CRC pathogenesis is not fully understood.
- Identifying novel therapeutic targets is crucial for improving CRC treatment outcomes.
Purpose of the Study:
- To elucidate the mechanism by which TPX2 influences colorectal cancer progression.
- To investigate the potential of targeting TPX2 as a therapeutic strategy for CRC.
- To explore the interplay between TPX2, p53, and autophagy in CRC cells.
Main Methods:
- Xenograft nude mouse models and human CRC cell lines (HCT116, RKO, SW480) were utilized.
- Experimental manipulations included TPX2 knockdown (sh-TPX2), overexpression (OE-TPX2), and treatment with autophagy modulators (3-MA, rapamycin).
- Assays performed: tumor growth assessment, immunohistochemistry, TUNEL staining, EdU staining, flow cytometry, transmission electron microscopy, and Western blot analysis.
Main Results:
- TPX2 inhibition (sh-TPX2) suppressed tumor growth, reduced proliferation (Ki67), increased apoptosis, and enhanced autophagy (LC3-II/LC3-I ratio) in HCT116 and RKO cells.
- TPX2 overexpression (OE-TPX2) showed opposite effects.
- Autophagy inhibition (3-MA) reversed the anti-cancer effects of sh-TPX2, while autophagy activation (rapamycin) enhanced them, indicating TPX2's role in mediating p53-induced autophagy for anti-CRC effects.
Conclusions:
- TPX2 knockdown activates p53, which in turn induces autophagy, leading to anti-colorectal cancer effects.
- TPX2 emerges as a promising therapeutic target for CRC.
- These findings offer new insights and potential strategies for CRC treatment.
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