Preferential Upregulation of AMOT-p80 Is Associated with YAP-Linked Resistance to 5-Fluorouracil and Oxaliplatin in
Yeho Kim1, Jin-Kyung Hong1, Mina Yeom1
1Department of Pharmacology, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Gyeonggi-do, Republic of Korea.
Abstract:
Resistance to 5-fluorouracil (5-FU) and oxaliplatin (OXA) remains an obstacle in colorectal cancer (CRC) therapy, but the upstream mechanisms enabling adaptive survival remain unclear. Angiomotin (AMOT), a Hippo-YAP regulator, is expressed as two major isoforms, p130 and p80, but the contribution of isoform-specific AMOT regulation to chemoresistance is unknown. RNA-seq of OXA-resistant cells identified AMOT as a candidate determinant, and its isoform-specific regulation and functional relevance were then examined in OXA- and 5-FU-resistant CRC sublines. AMOT-p80 was preferentially upregulated, whereas AMOT-p130 remained largely unchanged. Common AMOT pre-mRNA was elevated, whereas p130-specific pre-mRNA was unchanged, consistent with preferential transcriptional activation favoring the p80 isoform. Functionally, AMOT depletion minimally affected basal viability but significantly sensitized resistant cells to 5-FU or OXA, with increased apoptotic responses. AMOT silencing reduced nuclear YAP and lowered c-Myc and Cyclin D1 protein levels, whereas AMOT-p80 re-expression restored nuclear YAP, with recovery of c-Myc/Cyclin D1 levels and drug tolerance. YAP knockdown attenuated these outputs and blunted the additional effect of AMOT depletion. AMOT-p80 overexpression in parental cells increased c-Myc/Cyclin D1 protein levels and enhanced tolerance to 5-FU and OXA. These findings suggest that preferential AMOT-p80 upregulation is linked to YAP-associated chemoresistant phenotypes in CRC cells.
Insights
Preferential upregulation of Angiomotin-p80 (AMOT-p80) in colorectal cancer (CRC) cells promotes resistance to 5-fluorouracil (5-FU) and oxaliplatin (OXA) by activating the Hippo-YAP pathway.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Colorectal cancer (CRC) therapy faces challenges due to resistance to 5-fluorouracil (5-FU) and oxaliplatin (OXA).
- The underlying mechanisms of adaptive survival and chemoresistance in CRC are not fully understood.
- Angiomotin (AMOT), a regulator of the Hippo-YAP pathway, exists in two isoforms (p130 and p80), but their specific roles in chemoresistance are unknown.
Purpose of the Study:
- To investigate the isoform-specific regulation of AMOT in CRC chemoresistance.
- To determine the functional relevance of AMOT isoforms in mediating resistance to 5-FU and OXA.
- To elucidate the link between AMOT, the Hippo-YAP pathway, and chemoresistance in CRC.
Main Methods:
- RNA sequencing (RNA-seq) of oxaliplatin-resistant CRC cells.
- Analysis of AMOT isoform expression and pre-mRNA levels in 5-FU and OXA-resistant CRC sublines.
- Functional studies involving AMOT depletion and re-expression, YAP knockdown, and assessment of cell viability, apoptosis, and protein levels (c-Myc, Cyclin D1).
Main Results:
- AMOT-p80 was preferentially upregulated in resistant CRC cells, while AMOT-p130 levels remained unchanged.
- AMOT depletion sensitized resistant cells to 5-FU and OXA, increasing apoptosis.
- AMOT silencing reduced nuclear YAP, c-Myc, and Cyclin D1; AMOT-p80 re-expression restored these levels and drug tolerance.
- YAP knockdown attenuated AMOT's effects on chemoresistance.
Conclusions:
- Preferential upregulation of AMOT-p80 contributes to chemoresistance in CRC.
- The AMOT-p80/YAP axis promotes cell survival and tolerance to 5-FU and OXA in CRC.
- Targeting the AMOT-p80/YAP pathway may offer a therapeutic strategy to overcome chemoresistance in colorectal cancer.
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