Non-Metabolic Functions of PKM2 Contribute to Cervical Cancer Cell Proliferation Induced by the HPV16 E7 Oncoprotein
Pyruvate kinase M2 (PKM2) mainly catalyzes glycolysis, but it also exerts non-glycolytic functions in several cancers. While it has been shown to interact with the human papillomavirus 16 (HPV16) E7 oncoprotein, the functional significance of PKM2 in HPV-associated cervical cancer has been elusive....
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-03-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/13/3/433 |
| _version_ | 1797542158069137408 |
|---|---|
| author | Seoung-Ae Lee Charles Ho Madison Troxler Chin-Yo Lin Sang-Hyuk Chung |
| author_facet | Seoung-Ae Lee Charles Ho Madison Troxler Chin-Yo Lin Sang-Hyuk Chung |
| author_sort | Seoung-Ae Lee |
| collection | DOAJ |
| description | Pyruvate kinase M2 (PKM2) mainly catalyzes glycolysis, but it also exerts non-glycolytic functions in several cancers. While it has been shown to interact with the human papillomavirus 16 (HPV16) E7 oncoprotein, the functional significance of PKM2 in HPV-associated cervical cancer has been elusive. Here, we show that HPV16 E7 increased the expression of PKM2 in cervical cancer cells. TCGA data analyses revealed a higher level of PKM2 in HPV<sup>+</sup> than HPV<sup>−</sup> cervical cancers and a worse prognosis for patients with high PKM2 expression. Functionally, we demonstrate that shRNA-mediated PKM2 knockdown decreased the proliferation of HPV<sup>+</sup> SiHa cervical cancer cells. PKM2 knockdown also inhibited the E7-induced proliferation of cervical cancer cells. ML265 activating the pyruvate kinase function of PKM2 inhibited cell cycle progression and colony formation. ML265 treatments decreased phosphorylation of PKM2 at the Y105 position that has been associated with non-glycolytic functions. On the contrary, HPV16 E7 increased the PKM2 phosphorylation. Our results indicate that E7 increases PKM2 expression and activates a non-glycolytic function of PKM2 to promote cervical cancer cell proliferation. |
| first_indexed | 2024-03-10T13:26:41Z |
| format | Article |
| id | doaj.art-ffe2209b0cf2484a813ea31387b934e7 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T13:26:41Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-ffe2209b0cf2484a813ea31387b934e72023-11-21T09:39:03ZengMDPI AGViruses1999-49152021-03-0113343310.3390/v13030433Non-Metabolic Functions of PKM2 Contribute to Cervical Cancer Cell Proliferation Induced by the HPV16 E7 OncoproteinSeoung-Ae Lee0Charles Ho1Madison Troxler2Chin-Yo Lin3Sang-Hyuk Chung4Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USACenter for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USACenter for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USACenter for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USACenter for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USAPyruvate kinase M2 (PKM2) mainly catalyzes glycolysis, but it also exerts non-glycolytic functions in several cancers. While it has been shown to interact with the human papillomavirus 16 (HPV16) E7 oncoprotein, the functional significance of PKM2 in HPV-associated cervical cancer has been elusive. Here, we show that HPV16 E7 increased the expression of PKM2 in cervical cancer cells. TCGA data analyses revealed a higher level of PKM2 in HPV<sup>+</sup> than HPV<sup>−</sup> cervical cancers and a worse prognosis for patients with high PKM2 expression. Functionally, we demonstrate that shRNA-mediated PKM2 knockdown decreased the proliferation of HPV<sup>+</sup> SiHa cervical cancer cells. PKM2 knockdown also inhibited the E7-induced proliferation of cervical cancer cells. ML265 activating the pyruvate kinase function of PKM2 inhibited cell cycle progression and colony formation. ML265 treatments decreased phosphorylation of PKM2 at the Y105 position that has been associated with non-glycolytic functions. On the contrary, HPV16 E7 increased the PKM2 phosphorylation. Our results indicate that E7 increases PKM2 expression and activates a non-glycolytic function of PKM2 to promote cervical cancer cell proliferation.https://www.mdpi.com/1999-4915/13/3/433HPV16 E7cervical cancerPKM2ML265non-pyruvate kinase function |
| spellingShingle | Seoung-Ae Lee Charles Ho Madison Troxler Chin-Yo Lin Sang-Hyuk Chung Non-Metabolic Functions of PKM2 Contribute to Cervical Cancer Cell Proliferation Induced by the HPV16 E7 Oncoprotein Viruses HPV16 E7 cervical cancer PKM2 ML265 non-pyruvate kinase function |
| title | Non-Metabolic Functions of PKM2 Contribute to Cervical Cancer Cell Proliferation Induced by the HPV16 E7 Oncoprotein |
| title_full | Non-Metabolic Functions of PKM2 Contribute to Cervical Cancer Cell Proliferation Induced by the HPV16 E7 Oncoprotein |
| title_fullStr | Non-Metabolic Functions of PKM2 Contribute to Cervical Cancer Cell Proliferation Induced by the HPV16 E7 Oncoprotein |
| title_full_unstemmed | Non-Metabolic Functions of PKM2 Contribute to Cervical Cancer Cell Proliferation Induced by the HPV16 E7 Oncoprotein |
| title_short | Non-Metabolic Functions of PKM2 Contribute to Cervical Cancer Cell Proliferation Induced by the HPV16 E7 Oncoprotein |
| title_sort | non metabolic functions of pkm2 contribute to cervical cancer cell proliferation induced by the hpv16 e7 oncoprotein |
| topic | HPV16 E7 cervical cancer PKM2 ML265 non-pyruvate kinase function |
| url | https://www.mdpi.com/1999-4915/13/3/433 |
| work_keys_str_mv | AT seoungaelee nonmetabolicfunctionsofpkm2contributetocervicalcancercellproliferationinducedbythehpv16e7oncoprotein AT charlesho nonmetabolicfunctionsofpkm2contributetocervicalcancercellproliferationinducedbythehpv16e7oncoprotein AT madisontroxler nonmetabolicfunctionsofpkm2contributetocervicalcancercellproliferationinducedbythehpv16e7oncoprotein AT chinyolin nonmetabolicfunctionsofpkm2contributetocervicalcancercellproliferationinducedbythehpv16e7oncoprotein AT sanghyukchung nonmetabolicfunctionsofpkm2contributetocervicalcancercellproliferationinducedbythehpv16e7oncoprotein |