Targeting prohibitins with chemical ligands inhibits KRAS-mediated lung tumours

Abstract

KRAS is one of the most frequently mutated oncogenes in human non-small cell lung cancers (NSCLCs). RAS proteins trigger multiple effector signalling pathways including the highly conserved RAF-MAPK pathway. CRAF, a direct RAS effector protein, is required for KRAS-mediated tumourigenesis. Thus, the molecular mechanisms driving the activation of CRAF are intensively studied. Prohibitin 1 (PHB1) is an evolutionarily conserved adaptor protein and interaction of CRAF with PHB1 at the plasma membrane is essential for CRAF activation. Here, we demonstrate that PHB1 is highly expressed in NSCLC patients and correlates with poor survival. Targeting of PHB1 with two chemical ligands (rocaglamide and fluorizoline) inhibits epidermal growth factor (EGF)/RAS-induced CRAF activation. Consistently, treatment with rocaglamide inhibited proliferation, migration and anchorage-independent growth of KRAS-mutated lung carcinoma cell lines. Surprisingly, rocaglamide treatment inhibited Ras-GTP loading in KRAS-mutated cells as well as in EGF-stimulated cells. Rocaglamide treatment further prevented the oncogenic growth of KRAS-driven lung cancer allografts and xenografts in mouse models. Our results suggest rocaglamide as a RAS inhibitor and that targeting plasma membrane-associated PHB1 with chemical ligands would be a viable therapeutic strategy to combat KRAS-mediated NSCLCs.

Prohibitin promotes dedifferentiation and is a potential therapeutic target in neuroblastoma

“…It possible that the apparent G 1 arrest we observe in IMR-5/75 cells after PHB knockdown is due to impaired ERK activation in these cells. Indeed, previous reports have noted that both siRNA-mediated depletion of PHB and RocA treatment results in G 1 phase arrest and reduced cyclin D1 levels in Jurkat cells and in non-small cell lung cancer cells (19,20).…”

“…Given our findings that PHB overexpression was associated with several malignant features of neuroblastoma, including proliferation and dedifferentiation, we asked whether pharmacological disruption of PHB might help counter these processes. Rocaglamide A (RocA) can bind to PHB and has been reported to inhibit ERK activation and the growth and migration of a variety of cancer cells, including pancreatic cancer, non-small cell lung cancer, T cell leukemia, and melanoma (10,19,20,42). Although RocA has been reported to bind other molecules in addition to PHB, such as the translation factor eukaryotic initiation factor 4A (EIF4A) (43), and to inhibit autophagy in non-small cell lung cancer cells (44), we reasoned that its effects on PHB might prove useful in assessing the feasibility of inhibiting ERK activation in neuroblastoma in the absence of a more specific PHB inhibitor.…”

“…PHB has been reported to contribute to RAS/MAPK signaling by facilitating the activation of c-RAF by RAS in HeLa and CL1-0 cells (18). Several studies have sought to target PHB as a means of reducing signaling through the MAPK pathway to inhibit the migratory capacity or growth of T cell leukemia, pancreatic cancer, gallbladder cancer, and lung cancer cells (10,11,19,20). Here, we present evidence that PHB contributes to features of high-risk neuroblastoma tumors with 17q gain, such as enhanced proliferation, and promotes a state of cellular dedifferentiation.…”

Aberrant Expression of Prohibitin Is Related to Prognosis of Nasal Extranodal Natural Killer/T Cell Lymphoma, Nasal Type

“…In the nucleus, PHB controls the cell cycle, cell proliferation, and cell apoptosis by interacting with cell cycle-regulated proteins, transcription factors, and apoptosis-associated proteins [8][9][10]. The abnormal expression of PHB is closely associated with the development and progression of a number of human cancers [11][12][13][14]. The role of PHB in the development of nasal ENKTCL remains unknown.…”

Prohibitin participates in the HIRA complex to promote cell metastasis in breast cancer cell lines

“…The amino acid sequences of mouse and rat PHB are identical and differ from human PHB in only one single amino acid. Beyond its well-characterized function as chaperones in the mitochondrion to stabilize the mitochondrial proteins [1,2], PHB expression level is increased in cervix, breast, and lung cancers and is a potential therapeutic target in neuroblastoma and lung cancer [3][4][5][6][7]. However, the role of PHB in cancer progression remains controversial.…”