Combination of Metformin, Sodium Oxamate and Doxorubicin Induces Apoptosis and Autophagy in Colorectal Cancer Cells via Downregulation HIF-1α
Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide in both sexes. Current therapies include surgery, chemotherapy, and targeted therapy; however, prolonged exposure to chemical agents induces toxicity in patients and drug resistance. So, we implemented a therapeutic...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.594200/full |
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| author | Jossimar Coronel-Hernández Jossimar Coronel-Hernández Rebeca Salgado-García David Cantú-De León Nadia Jacobo-Herrera Oliver Millan-Catalan Izamary Delgado-Waldo Alma D. Campos-Parra Miguel Rodríguez-Morales Norma L. Delgado-Buenrostro Carlos Pérez-Plasencia Carlos Pérez-Plasencia |
| author_facet | Jossimar Coronel-Hernández Jossimar Coronel-Hernández Rebeca Salgado-García David Cantú-De León Nadia Jacobo-Herrera Oliver Millan-Catalan Izamary Delgado-Waldo Alma D. Campos-Parra Miguel Rodríguez-Morales Norma L. Delgado-Buenrostro Carlos Pérez-Plasencia Carlos Pérez-Plasencia |
| author_sort | Jossimar Coronel-Hernández |
| collection | DOAJ |
| description | Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide in both sexes. Current therapies include surgery, chemotherapy, and targeted therapy; however, prolonged exposure to chemical agents induces toxicity in patients and drug resistance. So, we implemented a therapeutic strategy based on the combination of doxorubicin, metformin, and sodium oxamate called triple therapy (Tt). We found that Tt significantly reduced proliferation by inhibiting the mTOR/AKT pathway and promoted apoptosis and autophagy in CRC derived cells compared with doxorubicin. Several autophagy genes were assessed by western blot; ULK1, ATG4, and LC3 II were overexpressed by Tt. Interestingly, ULK1 was the only one autophagy-related protein gradually overexpressed during Tt administration. Thus, we assumed that there was a post-transcriptional mechanism mediating by microRNAs that regulate UKL1 expression during autophagy activation. Through bioinformatics approaches, we ascertained that ULK1 could be targeted by mir-26a, which is overexpressed in advanced stages of CRC. In vitro experiments revealed that overexpression of mir-26a decreased significantly ULK1, mRNA, and protein expression. Contrariwise, the Tt recovered ULK1 expression by mir-26a decrease. Due to triple therapy repressed mir-26a expression, we hypothesized this drug combination could be involved in mir-26a transcription regulation. Consequently, we analyzed the mir-26a promoter sequence and found two HIF-1α transcription factor recognition sites. We developed two different HIF-1α stabilization models. Both showed mir-26a overexpression and ULK1 reduction in hypoxic conditions. Immunoprecipitation experiments were performed and HIF-1α enrichment was observed in mir-26a promoter. Surprisingly, Tt diminished HIF-1α detection and restored ULK1 mRNA expression. These results reveal an important regulation mechanism controlled by the signaling that activates HIF-1α and that in turn regulates mir-26a transcription. |
| first_indexed | 2024-12-17T22:33:39Z |
| format | Article |
| id | doaj.art-49cc4924fd5d4e71b7578226e0cca370 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-17T22:33:39Z |
| publishDate | 2021-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-49cc4924fd5d4e71b7578226e0cca3702022-12-21T21:30:08ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-05-011110.3389/fonc.2021.594200594200Combination of Metformin, Sodium Oxamate and Doxorubicin Induces Apoptosis and Autophagy in Colorectal Cancer Cells via Downregulation HIF-1αJossimar Coronel-Hernández0Jossimar Coronel-Hernández1Rebeca Salgado-García2David Cantú-De León3Nadia Jacobo-Herrera4Oliver Millan-Catalan5Izamary Delgado-Waldo6Alma D. Campos-Parra7Miguel Rodríguez-Morales8Norma L. Delgado-Buenrostro9Carlos Pérez-Plasencia10Carlos Pérez-Plasencia11Laboratorio de Genómica Funcional, Unidad de Biomedicina, FES-Iztacala, UNAM, Tlalnepantla, MexicoLaboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, MexicoLaboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, MexicoLaboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, MexicoINCMNSZ, Unidad de Bioquímica, Tlalpan, MexicoLaboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, MexicoLaboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, MexicoLaboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, MexicoLaboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, MexicoLaboratorio de Toxicología, Unidad de Biomedicina, FES-IZTACALA, UNAM, Tlalnepantla, MexicoLaboratorio de Genómica Funcional, Unidad de Biomedicina, FES-Iztacala, UNAM, Tlalnepantla, MexicoLaboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, MexicoColorectal cancer (CRC) is the third leading cause of cancer-related death worldwide in both sexes. Current therapies include surgery, chemotherapy, and targeted therapy; however, prolonged exposure to chemical agents induces toxicity in patients and drug resistance. So, we implemented a therapeutic strategy based on the combination of doxorubicin, metformin, and sodium oxamate called triple therapy (Tt). We found that Tt significantly reduced proliferation by inhibiting the mTOR/AKT pathway and promoted apoptosis and autophagy in CRC derived cells compared with doxorubicin. Several autophagy genes were assessed by western blot; ULK1, ATG4, and LC3 II were overexpressed by Tt. Interestingly, ULK1 was the only one autophagy-related protein gradually overexpressed during Tt administration. Thus, we assumed that there was a post-transcriptional mechanism mediating by microRNAs that regulate UKL1 expression during autophagy activation. Through bioinformatics approaches, we ascertained that ULK1 could be targeted by mir-26a, which is overexpressed in advanced stages of CRC. In vitro experiments revealed that overexpression of mir-26a decreased significantly ULK1, mRNA, and protein expression. Contrariwise, the Tt recovered ULK1 expression by mir-26a decrease. Due to triple therapy repressed mir-26a expression, we hypothesized this drug combination could be involved in mir-26a transcription regulation. Consequently, we analyzed the mir-26a promoter sequence and found two HIF-1α transcription factor recognition sites. We developed two different HIF-1α stabilization models. Both showed mir-26a overexpression and ULK1 reduction in hypoxic conditions. Immunoprecipitation experiments were performed and HIF-1α enrichment was observed in mir-26a promoter. Surprisingly, Tt diminished HIF-1α detection and restored ULK1 mRNA expression. These results reveal an important regulation mechanism controlled by the signaling that activates HIF-1α and that in turn regulates mir-26a transcription.https://www.frontiersin.org/articles/10.3389/fonc.2021.594200/fullHIF-1αautophagyULK1mir-26aAKTproliferation |
| spellingShingle | Jossimar Coronel-Hernández Jossimar Coronel-Hernández Rebeca Salgado-García David Cantú-De León Nadia Jacobo-Herrera Oliver Millan-Catalan Izamary Delgado-Waldo Alma D. Campos-Parra Miguel Rodríguez-Morales Norma L. Delgado-Buenrostro Carlos Pérez-Plasencia Carlos Pérez-Plasencia Combination of Metformin, Sodium Oxamate and Doxorubicin Induces Apoptosis and Autophagy in Colorectal Cancer Cells via Downregulation HIF-1α Frontiers in Oncology HIF-1α autophagy ULK1 mir-26a AKT proliferation |
| title | Combination of Metformin, Sodium Oxamate and Doxorubicin Induces Apoptosis and Autophagy in Colorectal Cancer Cells via Downregulation HIF-1α |
| title_full | Combination of Metformin, Sodium Oxamate and Doxorubicin Induces Apoptosis and Autophagy in Colorectal Cancer Cells via Downregulation HIF-1α |
| title_fullStr | Combination of Metformin, Sodium Oxamate and Doxorubicin Induces Apoptosis and Autophagy in Colorectal Cancer Cells via Downregulation HIF-1α |
| title_full_unstemmed | Combination of Metformin, Sodium Oxamate and Doxorubicin Induces Apoptosis and Autophagy in Colorectal Cancer Cells via Downregulation HIF-1α |
| title_short | Combination of Metformin, Sodium Oxamate and Doxorubicin Induces Apoptosis and Autophagy in Colorectal Cancer Cells via Downregulation HIF-1α |
| title_sort | combination of metformin sodium oxamate and doxorubicin induces apoptosis and autophagy in colorectal cancer cells via downregulation hif 1α |
| topic | HIF-1α autophagy ULK1 mir-26a AKT proliferation |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.594200/full |
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