RALB GTPase: a critical regulator of DR5 expression and TRAIL sensitivity in KRAS mutant colorectal cancer

RAS mutant (MT) metastatic colorectal cancer (mCRC) is resistant to MEK1/2 inhibition and remains a difficult-to-treat group. Therefore, there is an unmet need for novel treatment options for RAS MT mCRC. RALA and RALB GTPases function downstream of RAS and have been found to be key regulators of se...

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Vydáno v:	Cell death & disease Ročník 11; číslo 10; s. 930
Hlavní autoři:	Khawaja, Hajrah, Campbell, Andrew, Roberts, Jamie Z., Javadi, Arman, O’Reilly, Paul, McArt, Darragh, Allen, Wendy L., Majkut, Joanna, Rehm, Markus, Bardelli, Alberto, Di Nicolantonio, Federica, Scott, Christopher J., Kennedy, Richard, Vitale, Nicolas, Harrison, Timothy, Sansom, Owen J., Longley, Daniel B., Evergren, Emma, Van Schaeybroeck, Sandra
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 29.10.2020 Springer Nature B.V Nature Publishing Group
Témata:	13/2 13/31 13/89 14/19 38/109 38/79 42/70 631/67/1504/1885/1393 631/67/395 631/80/82/23 82/80 96/106 96/95 Antibodies Antineoplastic Combined Chemotherapy Protocols - pharmacology Apoptosis Benzimidazoles - administration & dosage Biochemistry Biomedical and Life Sciences Cancer Caspase-8 Cell Biology Cell Culture Cell death Cell surface Cellular Biology Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism DR5 protein GTP Phosphohydrolases - metabolism Humans Immunology K-Ras protein Life Sciences Lysosomes Metastases mRNA Mutants Mutation Proto-Oncogene Proteins p21(ras) - genetics Proto-Oncogene Proteins p21(ras) - metabolism ral GTP-Binding Proteins - antagonists & inhibitors ral GTP-Binding Proteins - biosynthesis ral GTP-Binding Proteins - genetics ral GTP-Binding Proteins - metabolism RalA protein Ras protein Receptors, TNF-Related Apoptosis-Inducing Ligand - agonists Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism Recombinant Proteins - pharmacology RNA, Messenger - genetics RNA, Messenger - metabolism RNA-mediated interference Signal transduction TNF-Related Apoptosis-Inducing Ligand - administration & dosage TNF-Related Apoptosis-Inducing Ligand - pharmacology Transfection Tumorigenesis
ISSN:	2041-4889, 2041-4889
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Shrnutí:	RAS mutant (MT) metastatic colorectal cancer (mCRC) is resistant to MEK1/2 inhibition and remains a difficult-to-treat group. Therefore, there is an unmet need for novel treatment options for RAS MT mCRC. RALA and RALB GTPases function downstream of RAS and have been found to be key regulators of several cell functions implicated in KRAS-driven tumorigenesis. However, their role as regulators of the apoptotic machinery remains to be elucidated. Here, we found that inhibition of RALB expression, but not RALA, resulted in Caspase-8-dependent cell death in KRAS MT CRC cells, which was not further increased following MEK1/2 inhibition. Proteomic analysis and mechanistic studies revealed that RALB depletion induced a marked upregulation of the pro-apoptotic cell surface TRAIL Death Receptor 5 (DR5) (also known as TRAIL-R2), primarily through modulating DR5 protein lysosomal degradation. Moreover, DR5 knockdown or knockout attenuated siRALB-induced apoptosis, confirming the role of the extrinsic apoptotic pathway as a regulator of siRALB-induced cell death. Importantly, TRAIL treatment resulted in the association of RALB with the death-inducing signalling complex (DISC) and targeting RALB using pharmacologic inhibition or RNAi approaches triggered a potent increase in TRAIL-induced cell death in KRAS MT CRC cells. Significantly, high RALB mRNA levels were found in the poor prognostic Colorectal Cancer Intrinsic Subtypes (CRIS)-B CRC subgroup. Collectively, this study provides to our knowledge the first evidence for a role for RALB in apoptotic priming and suggests that RALB inhibition may be a promising strategy to improve response to TRAIL treatment in poor prognostic RAS MT CRIS-B CRC.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC7596570
ISSN:	2041-4889 2041-4889
DOI:	10.1038/s41419-020-03131-3