Abstract 4366824: Protection of PDCD4 against doxorubicin-induced cardiotoxicity

Background: Programmed Cell Death 4 (PDCD4) is a tumor suppressor known for promoting apoptosis and inhibiting growth and protein translation in cancer cells. However, the role of PDCD4 in the heart remains elusive. This study explores PDCD4's regulation and function in the heart through genetic manipulation. Methods: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), neonatal mouse cardiomyocytes, and transgenic mice with constitutive cardiomyocyte-specific PDCD4 overexpression were used in this study. In vitro, PDCD4 expression was manipulated by plasmid-based overexpression or siRNA-mediated knockdown, and confirmed by Western blot. Subcellular localization of PDCD4 was assessed by immunofluorescence staining. Apoptosis was evaluated using cleaved-PARP immunoblotting and TUNEL staining. Cardiac function in mice was assessed by echocardiography. Results: In hiPSC-CMs and isolated neonatal cardiomyocytes, expression of PDCD4 is predominantly found in the nucleus, suggesting a possible role in nuclear signaling or gene regulation. Treatment of hiPSC-CMs with 1 μM doxorubicin (DOX) for 3 days significantly reduced PDCD4 expression. Functionally, PDCD4 overexpression attenuated DOX-induced apoptosis, as evidenced by decreased cleaved-PARP levels and fewer TUNEL-positive cells, whereas PDCD4 knockdown increased cell death, indicating a protective role under chemotherapeutic stress. PDCD4 expression decreased in mouse hearts during postnatal development. Transgenic mice with cardiomyocyte-specific PDCD4 overexpression showed normal heart weight, size, and function, without induced apoptosis under baseline conditions. We are currently investigating the potential cardioprotection of PDCD4 transgene against DOX induced acute and chronic cardiotoxicities. Conclusion: PDCD4 has a pro-apoptotic function in cancer cells but demonstrates an anti-apoptotic role in cardiomyocytes during chemotherapeutic stress in vitro. These observations indicate a context-dependent role for PDCD4 in cardioprotection, presenting it as a potential therapeutic target for reducing cardiotoxicity during cancer treatment.