Bortezomib exerts its anti-cancer activity through the regulation of Skp2/p53 axis in non-melanoma skin cancer cells and C. elegans
<p dir="ltr">Non-melanoma skin cancer (NMSC), encompassing basal and squamous cell carcinoma, is the most prevalent cancer in the United States. While surgical removal remains the conventional therapy with a 95% 5-year cure rate, there is a growing interest in exploring alternative t...
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2024
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| _version_ | 1864513509671305216 |
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| author | Kirti S. Prabhu (4246144) |
| author2 | Fareed Ahmad (134672) Shilpa Kuttikrishnan (3520079) Rari Leo (19325845) Tayyiba Akbar Ali (14152572) Mahmoud Izadi (12899508) Jericha M. Mateo (17563293) Majid Alam (14158959) Aamir Ahmad (233201) Ammira S. Al-Shabeeb Akil (18206017) Ajaz A. Bhat (12984701) Joerg Buddenkotte (6293584) Ehsan Pourkarimi (541179) Martin Steinhoff (5340194) Shahab Uddin (154400) |
| author2_role | author author author author author author author author author author author author author author |
| author_facet | Kirti S. Prabhu (4246144) Fareed Ahmad (134672) Shilpa Kuttikrishnan (3520079) Rari Leo (19325845) Tayyiba Akbar Ali (14152572) Mahmoud Izadi (12899508) Jericha M. Mateo (17563293) Majid Alam (14158959) Aamir Ahmad (233201) Ammira S. Al-Shabeeb Akil (18206017) Ajaz A. Bhat (12984701) Joerg Buddenkotte (6293584) Ehsan Pourkarimi (541179) Martin Steinhoff (5340194) Shahab Uddin (154400) |
| author_role | author |
| dc.creator.none.fl_str_mv | Kirti S. Prabhu (4246144) Fareed Ahmad (134672) Shilpa Kuttikrishnan (3520079) Rari Leo (19325845) Tayyiba Akbar Ali (14152572) Mahmoud Izadi (12899508) Jericha M. Mateo (17563293) Majid Alam (14158959) Aamir Ahmad (233201) Ammira S. Al-Shabeeb Akil (18206017) Ajaz A. Bhat (12984701) Joerg Buddenkotte (6293584) Ehsan Pourkarimi (541179) Martin Steinhoff (5340194) Shahab Uddin (154400) |
| dc.date.none.fl_str_mv | 2024-05-09T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41420-024-01992-7 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Bortezomib_exerts_its_anti-cancer_activity_through_the_regulation_of_Skp2_p53_axis_in_non-melanoma_skin_cancer_cells_and_C_elegans/26491129 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences Non-Melanoma Skin Cancer (NMSC) Basal Cell Carcinoma Squamous Cell Carcinoma Mitochondrial Permeability Cytochrome C Reactive Oxygen Species (ROS) Cancer Research |
| dc.title.none.fl_str_mv | Bortezomib exerts its anti-cancer activity through the regulation of Skp2/p53 axis in non-melanoma skin cancer cells and C. elegans |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Non-melanoma skin cancer (NMSC), encompassing basal and squamous cell carcinoma, is the most prevalent cancer in the United States. While surgical removal remains the conventional therapy with a 95% 5-year cure rate, there is a growing interest in exploring alternative treatment strategies. In this study, we investigated the role of Bortezomib (BTZ), a proteasome inhibitor, in NMSC. Using two NMSC cell lines (A431 and A388), we examined the effects of BTZ treatment. Our results demonstrated that 48 h of BTZ treatment led to downregulating Skp2 expression in both A431 and A388 cells while upregulating p53 expression, specifically in A388 cells. These alterations resulted in impaired cellular growth and caspase-dependent cell death. Silencing Skp2 in A388 cells with siRNA confirmed the upregulation of p53 as a direct target. Furthermore, BTZ treatment increased the Bax to Bcl-2 ratio, promoting mitochondrial permeability and the subsequent release of cytochrome C, thereby activating caspases. We also found that BTZ exerted its antitumor effects by generating reactive oxygen species (ROS), as blocking ROS production significantly reduced BTZ-induced apoptotic cell death. Interestingly, BTZ treatment induced autophagy, which is evident from the increased expression of microtubule-associated proteins nucleoporin p62 and LC-3A/B. In addition to cell lines, we assessed the impact of BTZ in an in vivo setting using Caenorhabditis elegans (C. elegans). Our findings demonstrated that BTZ induced germline apoptosis in worms even at low concentrations. Notably, this increased apoptosis was mediated through the activity of CEP-1, the worm’s counterpart to mammalian p53. In summary, our study elucidated the molecular mechanism underlying BTZ-induced apoptosis in NMSC cell lines and C. elegans. By targeting the skp2/p53 axis, inducing mitochondrial permeability, generating ROS, and promoting autophagy, BTZ demonstrates promising anti-cancer activity in NMSC. These findings provide novel insights into potential therapeutic strategies for controlling the unregulated growth of NMSC.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Death Discovery<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41420-024-01992-7" target="_blank">https://dx.doi.org/10.1038/s41420-024-01992-7</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_8d34a901fd2efce2dcf878328965f7f6 |
| identifier_str_mv | 10.1038/s41420-024-01992-7 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26491129 |
| publishDate | 2024 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Bortezomib exerts its anti-cancer activity through the regulation of Skp2/p53 axis in non-melanoma skin cancer cells and C. elegansKirti S. Prabhu (4246144)Fareed Ahmad (134672)Shilpa Kuttikrishnan (3520079)Rari Leo (19325845)Tayyiba Akbar Ali (14152572)Mahmoud Izadi (12899508)Jericha M. Mateo (17563293)Majid Alam (14158959)Aamir Ahmad (233201)Ammira S. Al-Shabeeb Akil (18206017)Ajaz A. Bhat (12984701)Joerg Buddenkotte (6293584)Ehsan Pourkarimi (541179)Martin Steinhoff (5340194)Shahab Uddin (154400)Biomedical and clinical sciencesClinical sciencesOncology and carcinogenesisPharmacology and pharmaceutical sciencesNon-Melanoma Skin Cancer (NMSC)Basal Cell CarcinomaSquamous Cell CarcinomaMitochondrial PermeabilityCytochrome CReactive Oxygen Species (ROS)Cancer Research<p dir="ltr">Non-melanoma skin cancer (NMSC), encompassing basal and squamous cell carcinoma, is the most prevalent cancer in the United States. While surgical removal remains the conventional therapy with a 95% 5-year cure rate, there is a growing interest in exploring alternative treatment strategies. In this study, we investigated the role of Bortezomib (BTZ), a proteasome inhibitor, in NMSC. Using two NMSC cell lines (A431 and A388), we examined the effects of BTZ treatment. Our results demonstrated that 48 h of BTZ treatment led to downregulating Skp2 expression in both A431 and A388 cells while upregulating p53 expression, specifically in A388 cells. These alterations resulted in impaired cellular growth and caspase-dependent cell death. Silencing Skp2 in A388 cells with siRNA confirmed the upregulation of p53 as a direct target. Furthermore, BTZ treatment increased the Bax to Bcl-2 ratio, promoting mitochondrial permeability and the subsequent release of cytochrome C, thereby activating caspases. We also found that BTZ exerted its antitumor effects by generating reactive oxygen species (ROS), as blocking ROS production significantly reduced BTZ-induced apoptotic cell death. Interestingly, BTZ treatment induced autophagy, which is evident from the increased expression of microtubule-associated proteins nucleoporin p62 and LC-3A/B. In addition to cell lines, we assessed the impact of BTZ in an in vivo setting using Caenorhabditis elegans (C. elegans). Our findings demonstrated that BTZ induced germline apoptosis in worms even at low concentrations. Notably, this increased apoptosis was mediated through the activity of CEP-1, the worm’s counterpart to mammalian p53. In summary, our study elucidated the molecular mechanism underlying BTZ-induced apoptosis in NMSC cell lines and C. elegans. By targeting the skp2/p53 axis, inducing mitochondrial permeability, generating ROS, and promoting autophagy, BTZ demonstrates promising anti-cancer activity in NMSC. These findings provide novel insights into potential therapeutic strategies for controlling the unregulated growth of NMSC.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Death Discovery<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41420-024-01992-7" target="_blank">https://dx.doi.org/10.1038/s41420-024-01992-7</a></p>2024-05-09T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41420-024-01992-7https://figshare.com/articles/journal_contribution/Bortezomib_exerts_its_anti-cancer_activity_through_the_regulation_of_Skp2_p53_axis_in_non-melanoma_skin_cancer_cells_and_C_elegans/26491129CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/264911292024-05-09T03:00:00Z |
| spellingShingle | Bortezomib exerts its anti-cancer activity through the regulation of Skp2/p53 axis in non-melanoma skin cancer cells and C. elegans Kirti S. Prabhu (4246144) Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences Non-Melanoma Skin Cancer (NMSC) Basal Cell Carcinoma Squamous Cell Carcinoma Mitochondrial Permeability Cytochrome C Reactive Oxygen Species (ROS) Cancer Research |
| status_str | publishedVersion |
| title | Bortezomib exerts its anti-cancer activity through the regulation of Skp2/p53 axis in non-melanoma skin cancer cells and C. elegans |
| title_full | Bortezomib exerts its anti-cancer activity through the regulation of Skp2/p53 axis in non-melanoma skin cancer cells and C. elegans |
| title_fullStr | Bortezomib exerts its anti-cancer activity through the regulation of Skp2/p53 axis in non-melanoma skin cancer cells and C. elegans |
| title_full_unstemmed | Bortezomib exerts its anti-cancer activity through the regulation of Skp2/p53 axis in non-melanoma skin cancer cells and C. elegans |
| title_short | Bortezomib exerts its anti-cancer activity through the regulation of Skp2/p53 axis in non-melanoma skin cancer cells and C. elegans |
| title_sort | Bortezomib exerts its anti-cancer activity through the regulation of Skp2/p53 axis in non-melanoma skin cancer cells and C. elegans |
| topic | Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences Non-Melanoma Skin Cancer (NMSC) Basal Cell Carcinoma Squamous Cell Carcinoma Mitochondrial Permeability Cytochrome C Reactive Oxygen Species (ROS) Cancer Research |