Background Targeting AKT suppresses tumor growth through inducing apoptosis, however, during which whether other forms of cell death occurring is poorly understood. Methods The effects of increasing PARP1 dependent cell death (parthanatos) induced by inhibiting AKT on cell proliferation were determined by CCK-8 assay, colony formation assay, Hoechst 33,258 staining and analysis of apoptotic cells by flow cytometry. For the detailed mechanisms during this process, Western blot analysis, qRT-PCR analysis, immunofluorescence and co-immunoprecipitation were performed. Moreover, the inhibition of tumor growth by inducing p53/SIRT6/PARP1-dependent parthanatos was further verified in the xenograft mouse model. Results For the first time, we identified that inhibiting AKT triggered parthanatos, a new form of regulated cell death, leading to colon cancer growth suppression. For the mechanism investigation, we found that after pharmacological or genetic AKT inhibition, p53 interacted with SIRT6 and PARP1 directly to activate it, and promoted the formation of PAR polymer. Subsequently, PAR polymer transported to outer membrane of mitochondria and resulted in AIF releasing and translocating to nucleus thus promoting cell death. While, blocking PARP1 activity significantly rescued colon cancer from death. Furthermore, p53 deletion or mutation eliminated PAR polymer formation, AIF translocation, and PARP1 dependent cell death, which was promoted by overexpression of SIRT6. Meanwhile, reactive oxygen species production was elevated after inhibition of AKT, which might also play a role in the occurrence of parthanatos. In addition, inhibiting AKT initiated protective autophagy simultaneously, which advanced tumor survival and growth. Conclusion Our findings demonstrated that AKT inhibition induced p53-SIRT6-PARP1 complex formation and the activation of parthanatos, which can be recognized as a novel potential therapeutic strategy for cancer.

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N-methyladenosine (m6A) is the abundant RNA modification in colorectal cancer. However, the biological significance of m6A methylation of LncRNA CARMN remains unknown in colorectal cancer, especially for mutant p53 Gain-of-function. Here, we found that CARMN reduced in the colorectal cancer patients with mutant p53, due to its rich m6A methylation, which promotes cancer proliferation, invasion, and metastasis in vitro and in vivo. Deeper investigation illustrates that ALKBH5 directly demethylated m6A level of CARMN at 477 sites, which maintains CARMN with a higher expression level. However, mutant p53 binds to the promoter of ALKBH5 to prevent its transcription, results in the high level m6A methylation of CARMN, subsequently read by YTHDF2/YTHDF3 and degraded. Meantime, overexpressing CARMN significantly suppressed colorectal cancer progression in vitro and in vivo. In addition, miR-5683 was identified as a direct downstream target of LncRNA CARMN, which plays anti-tumor effect through cooperating with CARMN to down-regulate FGF2 expression. Our study revealed the regulator and functional mechanism of CARMN in colorectal cancer with mutant p53, which may highlight a demethylation-based approach for the diagnosis and therapy of cancer.