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- Title
Therapy‐induced senescent cancer cells exhibit complement activation and increased complement regulatory protein expression.
- Authors
Abu‐Humaidan, Anas HA; Ismail, Mohammad A; Ahmad, Fatima M; Al Shboul, Sofian; Barham, Raghad; Tadros, Joud S; Alhesa, Ahmad; El‐Sadoni, Mohammed; Alotaibi, Moureq R; Ababneh, Nidaa A; Saleh, Tareq
- Abstract
Therapy‐induced senescence (TIS) is a primary response to chemotherapy, contributing to untoward treatment outcomes such as evasion of immunosurveillance. Despite the established role of the complement system in the immune response to cancer, the role of complement in mediating the immune response against senescent tumor cells remains poorly understood. To explore this relationship, we exposed lung adenocarcinoma (A549), breast adenocarcinoma (MCF7) and pancreatic carcinoma (Panc‐1) cell lines to sublethal doses of either etoposide or doxorubicin to trigger TIS. Identification of TIS was based on morphological changes, upregulation of the senescence‐associated β‐galactosidase, p21Cip1 induction and lamin B1 downregulation. Using immunofluorescence microscopy, quantitative PCR, ELISA of conditioned media and in silico analysis, we investigated complement activation, complement protein expression, C3 levels in the conditioned media of senescent cells and secreted complement proteins as part of the senescence‐associated secretory phenotype (SASP), respectively. In cell lines undergoing TIS, complement‐related changes included (i) activation of the terminal pathway, evidenced by the deposition of C5b‐9 on senescent cells; (ii) an increase in the expression of CD59 and complement factor H and (iii) in A549 cells, an elevation in the expression of C3 with its secretion into the medium. In addition, increased C3 expression was observed in breast cancer samples expressing TIS hallmarks following exposure to neoadjuvant chemotherapy. In conclusion, TIS led to the activation of complement, upregulation of complement regulatory proteins and increased C3 expression. Complement appears to play a role in shaping the cancer microenvironment upon senescence induction.
- Subjects
COMPLEMENT activation; PROTEIN expression; BREAST; COMPLEMENT factor H; COMPLEMENT receptors; CANCER cells; NEOADJUVANT chemotherapy
- Publication
Immunology & Cell Biology, 2024, Vol 102, Issue 4, p240
- ISSN
0818-9641
- Publication type
Article
- DOI
10.1111/imcb.12727