Platycodin D confers oxaliplatin Resistance in Colorectal Cancer by activating the LATS2/YAP1 axis of the hippo signaling pathway

Abstract

Oxaliplatin-based therapy is used as a first-line drug to treat metastatic colorectal cancer. However, long-term and repeated drug treatment resulted in drug resistance and the failure of chemotherapy. Various natural compounds were previously reported to act as chemosensitizers to reverse drug resistance. In this study, we found that platycodin D (PD), a saponin found in Platycodon grandiflorum, inhibited LoVo and OR-LoVo cells proliferation, invasion, and migration ability. Our results indicated that combined treatment of oxaliplatin with PD dramatically reduced the cellular proliferation in both LoVo and OR-LoVo cells. Furthermore, treatment with PD dose-dependently decreased LATS2/YAP1 hippo signaling and survival marker p-AKT expression, as well as increased cyclin-dependent kinase inhibitor proteins such as p21 and p27 expression. Importantly, PD activates and promotes YAP1 degradation through the ubiquitination and proteasome pathway. The nuclear transactivation of YAP was significantly reduced under PD treatment, leading to transcriptional inhibition of the downstream genes regulating cell proliferation, pro-survival, and metastasis. In conclusion, our results showed that PD is suitable as a promising agent for overcoming oxaliplatin-resistant colorectal cancer.

Comparative Assessment and High-Throughput Drug-Combination Profiling of TEAD-Palmitoylation Inhibitors in Hippo Pathway Deficient Mesothelioma

“…Consistent with its central tumor-suppressor role, somatic alterations of the core Hippo pathway genes have been observed in various cancer types, including malignant pleural mesothelioma, cervical squamous cell carcinoma, meningioma, head and neck squamous cell carcinoma, uveal melanoma, and cholangiocarcinoma, among others [6][7][8]. In about 30-40% of malignant pleural mesothelioma cases, for example, the NF2 (Neurofibromatosis type 2) tumor suppressor gene is somatically inactivated, leading to defective recruitment 2 of 16 of LATS1/2 kinases to the plasma membrane and impaired Hippo signaling [9,10].…”

“…Aberrant activation of TEAD-family transcription factors (TEADs) is a central determinant of oncogenic transformation in cancers characterized by dysregulation of the Hippo signaling pathway. Genetic inactivation of core genes within this tumor-suppressor kinase cascade (for example, about 35% to 40% of malignant pleural mesotheliomas cases carry an inactivating mutations at the neurofibromatosis 2, NF2, locus) or genetic amplification of YAP/TAZ transcriptional regulator (for example, more than 15% of cervical squamous cell carcinoma are driven by YAP/TAZ amplification) converge on TEAD transcription factors to establish an oncogenic transcriptional program that promotes uncontrolled cell proliferation [6,10]. This convergence highlights TEAD's centrality and establishes TEAD as a classic example of "non-oncogene addiction" that could be targeted therapeutically [41].…”

Targeted Treatment against Cancer Stem Cells in Colorectal Cancer

“…In CRC cell models, constitutive YAP activation reinforced the expression of the stemness biomarkers and regulators ALDH1A3, LGR5, and OCT4. The four main components of the Hippo pathway, MST1, LATS1/2, YAP, and TAZ, have also been shown to play a role in the development of chemoresistance, such as to 5-fluoruracil and oxalipatin [ 117 , 118 ].…”

Discovery of the Next-Generation Platinum-Based Anticancer Agents for Combating Oxaliplatin-Induced Drug Resistance

“…Regarding the mechanism of cancers being resistant to oxaliplatin, scientists have discovered several important biological pathways involved in the development of drug resistance. These include but are not limited to (1) the development of apoptosis inhibition and immunological tolerance, (2) nonspecific drug efflux and detoxification, and (3) specific DNA damage repair. − To overcome the daunting challenge posed by oxaliplatin resistance, scientists are committed to finding chemosensitizers that can effectively restore oxaliplatin sensitivity. − These approaches are mainly based on the resistance mechanisms relevant to the immune and apoptosis evasion of tumor cells. For instance, Liu’s group reported that the natural compound scutellarin could resensitize oxaliplatin activity against resistant CRC cells through ininhibition of the PKM2 enzyme, which is responsible for PDL-1 expression (Figure ).…”