Metastasis represents a major challenge in the treatment of clinical colorectal cancer (CRC), and anoikis resistance enables cancer cell dissemination. This study identifies Calcium/calmodulin-dependent protein kinase I (CAMK1) as a crucial regulator of anoikis in CRC progression. We analyzed CAMK1 expression in CRC tissues and its correlation with patient prognosis. In vitro, CAMK1 was overexpressed in CRC cell lines to assess its effects on proliferation, migration, invasion, and anoikis resistance. In vivo, mouse models were established to evaluate the impact of CAMK1 overexpression on tumor growth and liver metastasis. Mechanistically, we examined the interaction between CAMK1 and Phosphoinositide 3-kinase (PI3K), as well as the phosphorylation of PI3K and the activation of the downstream Protein kinase B (AKT) pathway. Mitochondrial function indicators were simultaneously measured: membrane potential, reactive oxygen species (ROS) production, and apoptosis markers, including the Bax/Bcl-2 ratio and Caspase-3 activation. Rescue experiments were conducted using the PI3K activator 740 Y-P. CAMK1 expression was significantly downregulated in CRC tissues, and low CAMK1 levels correlated with poor patient prognosis. In vitro, overexpression of CAMK1 significantly inhibited the malignant phenotypes of CRC cells and sensitized them to anoikis. Consistently, CAMK1 overexpression suppressed tumor growth and hepatic metastasis in mouse models. Mechanistically, CAMK1 interacted with PI3K, inhibiting its phosphorylation and subsequent AKT pathway activation. This inhibition induced mitochondrial dysfunction, characterized by depolarization of the mitochondrial membrane potential and increased ROS production, and promoted apoptosis, as evidenced by an elevated Bax/Bcl-2 ratio and Caspase-3 activation. Notably, the PI3K activator 740 Y-P effectively reversed the pro-anoikis effects and mitochondrial alterations induced by CAMK1, confirming the pivotal role of the PI3K/AKT pathway in this regulation. CAMK1 functions as a novel tumor suppressor in CRC. It constrains anoikis resistance and metastasis by inhibiting the PI3K/AKT signaling pathway, thereby disrupting mitochondrial function. These findings highlight the dual potential of CAMK1 as both a prognostic biomarker and therapeutic target in colorectal cancer.
Feng et al. (2026) studied this question.