Eikanger Morgan M, Sane Sanam, Schraufnagel Kate S, Slunecka John L, Potts Rashaun A, Freeling Jessica, Sereda Grigoriy, Rasulev Bakhtiyor, Brockstein Reed L, Emon M A Bashar, Saif M Taher A, Rezvani Khosrow
University of South Dakota Sanford School of Medicine.
University of South Dakota College of Arts and Sciences.
Res Sq. 2024 Oct 25:rs.3.rs-5199838. doi: 10.21203/rs.3.rs-5199838/v1.
Despite considerable advances to improve colorectal cancer (CRC) survival over the last decade, therapeutic challenges remain due to the rapid metastatic dissemination of primary tumors and screening limitations. Meanwhile, the rise of CRC in younger adults (Early-onset CRC), commonly diagnosed with a metastatic form of the disease, shows the pressing need to develop more effective targeted therapies to decrease the high mortality rates associated with metastatic disease. Hyperactivation of the Rictor-mTORC2-AKT signaling pathway drives key metastatic players in diverse malignant tumors, including early- and late-onset colorectal cancer. Selective mTORC2 inhibitors are becoming a potential treatment strategy for CRC due to the therapeutic limitations of mTORC1 inhibitors. Veratridine (VTD), a lipid-soluble alkaloid extracted from Liliaceae plants, can transcriptionally increase UBXN2A, which induces 26S proteasomal degradation of the Rictor protein, a key member in the mTORC2 complex. Destabilization of Rictor protein by VTD decreases Akt phosphorylation on Ser, which is responsible for metastatic signaling downstream of the mTORC2 pathway in diverse malignant tumors. VTD decreases the population of metastatic colon cancer stem cells and functions as an angiogenesis inhibitor. VTD effectively reduces the spheroid growth rate and restricts cell migration. Live cell migration and invasion assays alongside biomechanical-force-based experiments revealed that VTD suppresses colon cancer cell invasiveness and the ensuing risk of tumor metastasis. A CRC mouse model that mimics the natural stages of human sporadic CRC revealed that VTD treatment significantly decreases tumor growth in a UBXN2A-dependent manner. This study showed a novel mechanistic connection between a ubiquitin-like protein and mTORC2-dependent migration and invasion in CRC tumors. This study revealed the therapeutic benefit of selective inhibition of Rictor in CRC, particularly in tumors with a hyperactive Rictor-mTORC2 signaling pathway. Finally, this study opened a new platform for repurposing VTD, a supplemental anti-hypertension molecule, into an effective targeted therapy in CRC tumors.
尽管在过去十年中，为提高结直肠癌（CRC）生存率已取得了显著进展，但由于原发性肿瘤的快速转移扩散和筛查局限性，治疗挑战依然存在。与此同时，年轻成年人中结直肠癌（早发性CRC）的发病率不断上升，这些患者通常被诊断为转移性疾病，这表明迫切需要开发更有效的靶向治疗方法，以降低与转移性疾病相关的高死亡率。Rictor-mTORC2-AKT信号通路的过度激活驱动了多种恶性肿瘤（包括早发性和晚发性结直肠癌）中的关键转移因子。由于mTORC1抑制剂的治疗局限性，选择性mTORC2抑制剂正成为CRC的一种潜在治疗策略。藜芦碱（VTD）是一种从百合科植物中提取的脂溶性生物碱，可转录性增加UBXN2A，从而诱导mTORC2复合物的关键成员Rictor蛋白的26S蛋白酶体降解。VTD使Rictor蛋白不稳定，降低了丝氨酸上的Akt磷酸化，而这种磷酸化在多种恶性肿瘤中负责mTORC2通路下游的转移信号传导。VTD减少了转移性结肠癌干细胞的数量，并起到血管生成抑制剂的作用。VTD有效降低了球体生长速率并限制了细胞迁移。活细胞迁移和侵袭试验以及基于生物力学力的实验表明，VTD抑制结肠癌细胞的侵袭性以及随之而来的肿瘤转移风险。一个模拟人类散发性CRC自然阶段的CRC小鼠模型显示，VTD治疗以UBXN2A依赖的方式显著降低肿瘤生长。这项研究揭示了一种泛素样蛋白与CRC肿瘤中mTORC2依赖的迁移和侵袭之间的新型机制联系。这项研究揭示了选择性抑制Rictor在CRC中的治疗益处，特别是在具有过度活跃的Rictor-mTORC2信号通路的肿瘤中。最后，这项研究为将VTD（一种补充性抗高血压分子）重新用作CRC肿瘤的有效靶向治疗开辟了一个新平台。
