CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer
As the world’s fourth most deadly cancer, colorectal cancer (CRC) still needed the novel therapeutic drugs and target urgently. Although cyclin-dependent kinase 12 (CDK12) has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in CRC remain la...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824000410 |
| _version_ | 1797291809809891328 |
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| author | Zimei Wu Wenxin Zhang Lu Chen Tianxiao Wang Xinhai Wang Huanying Shi Liudi Zhang Mingkang Zhong Xiaojin Shi Xiang Mao Haifei Chen Qunyi Li |
| author_facet | Zimei Wu Wenxin Zhang Lu Chen Tianxiao Wang Xinhai Wang Huanying Shi Liudi Zhang Mingkang Zhong Xiaojin Shi Xiang Mao Haifei Chen Qunyi Li |
| author_sort | Zimei Wu |
| collection | DOAJ |
| description | As the world’s fourth most deadly cancer, colorectal cancer (CRC) still needed the novel therapeutic drugs and target urgently. Although cyclin-dependent kinase 12 (CDK12) has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in CRC remain largely unknown. Here, we found that suppression of CDK12 inhibited tumor growth in CRC by inducing apoptosis. And CDK12 inhibition triggered autophagy by upregulating autophagy related gene 7 (ATG7) expression. Inhibition of autophagy by ATG7 knockdown and chloroquine (CQ) further decreased cell viability induced by CDK12 inhibition. Further mechanism exploration showed that CDK12 interacted with protein kinase B (AKT) regulated autophagy via AKT/forkhead box O3 (AKT/FOXO3) pathway. FOXO3 transcriptionally upregulated ATG7 expression and autophagy when CDK12 inhibition in CRC. Level of CDK12 and p-FOXO3/FOXO3 ratio were correlated with survival in CRC patients. Moreover, CDK12 inhibition improved the efficacy of anti-programmed cell death 1(PD-1) therapy in CRC murine models by enhancing CD8 + T cells infiltration. Thus, our study founded that CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in CRC. We revealed the roles of CDK12/FOXO3/ATG7 in regulating CRC progression, suggesting potential biomarkers and therapeutic target for CRC. |
| first_indexed | 2024-03-07T19:42:09Z |
| format | Article |
| id | doaj.art-089cc82cf7f3400e93914f9275abe993 |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-07T19:42:09Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-089cc82cf7f3400e93914f9275abe9932024-02-29T05:18:09ZengElsevierPharmacological Research1096-11862024-03-01201107097CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancerZimei Wu0Wenxin Zhang1Lu Chen2Tianxiao Wang3Xinhai Wang4Huanying Shi5Liudi Zhang6Mingkang Zhong7Xiaojin Shi8Xiang Mao9Haifei Chen10Qunyi Li11Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, ChinaDepartment of Pharmacy, Huashan Hospital, Fudan University, Shanghai, ChinaDepartment of Pharmacy, Huashan Hospital, Fudan University, Shanghai, ChinaDepartment of Pharmacy, Huashan Hospital, Fudan University, Shanghai, ChinaDepartment of Surgery, Huashan Hospital, Fudan University, Shanghai, ChinaDepartment of Pharmacy, Huashan Hospital, Fudan University, Shanghai, ChinaDepartment of Pharmacy, Huashan Hospital, Fudan University, Shanghai, ChinaDepartment of Pharmacy, Huashan Hospital, Fudan University, Shanghai, ChinaDepartment of Pharmacy, Huashan Hospital, Fudan University, Shanghai, ChinaDepartment of Surgery, Huashan Hospital, Fudan University, Shanghai, China; Correspondence to: 12 Wu Lu Mu Qi M Road, Shanghai 200040, China.Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China; Correspondence to: 12 Wu Lu Mu Qi M Road, Shanghai 200040, China.Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China; Correspondence to: 12 Wu Lu Mu Qi M Road, Shanghai 200040, China.As the world’s fourth most deadly cancer, colorectal cancer (CRC) still needed the novel therapeutic drugs and target urgently. Although cyclin-dependent kinase 12 (CDK12) has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in CRC remain largely unknown. Here, we found that suppression of CDK12 inhibited tumor growth in CRC by inducing apoptosis. And CDK12 inhibition triggered autophagy by upregulating autophagy related gene 7 (ATG7) expression. Inhibition of autophagy by ATG7 knockdown and chloroquine (CQ) further decreased cell viability induced by CDK12 inhibition. Further mechanism exploration showed that CDK12 interacted with protein kinase B (AKT) regulated autophagy via AKT/forkhead box O3 (AKT/FOXO3) pathway. FOXO3 transcriptionally upregulated ATG7 expression and autophagy when CDK12 inhibition in CRC. Level of CDK12 and p-FOXO3/FOXO3 ratio were correlated with survival in CRC patients. Moreover, CDK12 inhibition improved the efficacy of anti-programmed cell death 1(PD-1) therapy in CRC murine models by enhancing CD8 + T cells infiltration. Thus, our study founded that CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in CRC. We revealed the roles of CDK12/FOXO3/ATG7 in regulating CRC progression, suggesting potential biomarkers and therapeutic target for CRC.http://www.sciencedirect.com/science/article/pii/S1043661824000410Cyclin-dependent kinase 12Autophagy related gene 7Colorectal cancerProgrammed cell death 1 |
| spellingShingle | Zimei Wu Wenxin Zhang Lu Chen Tianxiao Wang Xinhai Wang Huanying Shi Liudi Zhang Mingkang Zhong Xiaojin Shi Xiang Mao Haifei Chen Qunyi Li CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer Pharmacological Research Cyclin-dependent kinase 12 Autophagy related gene 7 Colorectal cancer Programmed cell death 1 |
| title | CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer |
| title_full | CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer |
| title_fullStr | CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer |
| title_full_unstemmed | CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer |
| title_short | CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer |
| title_sort | cdk12 inhibition upregulates atg7 triggering autophagy via akt foxo3 pathway and enhances anti pd 1 efficacy in colorectal cancer |
| topic | Cyclin-dependent kinase 12 Autophagy related gene 7 Colorectal cancer Programmed cell death 1 |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824000410 |
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