Targeting K-Ras and Apoptosis-driven Cellular Transformation in Cancer

Overview

Journal Cell Death Discov

Date 2021 Apr 15

PMID 33854056

Citations 9

Authors

Isha Godwin

Nikhil Ponnoor Anto

Smitha V Bava

Mani Shankar Babu

Goodwin G Jinesh

Affiliations

Soon will be listed here.

Abstract

Cellular transformation is a major event that helps cells to evade apoptosis, genomic instability checkpoints, and immune surveillance to initiate tumorigenesis and to promote progression by cancer stem cell expansion. However, the key molecular players that govern cellular transformation and ways to target cellular transformation for therapy are poorly understood to date. Here we draw key evidences from the literature on K-Ras-driven cellular transformation in the context of apoptosis to shed light on the key players that are required for cellular transformation and explain how aiming p53 could be useful to target cellular transformation. The defects in key apoptosis regulators such as p53, Bax, and Bak lead to apoptosis evasion, cellular transformation, and genomic instability to further lead to stemness, tumorigenesis, and metastasis via c-Myc-dependent transcription. Therefore enabling key apoptotic checkpoints in combination with K-Ras inhibitors will be a promising therapeutic target in cancer therapy.

Citing Articles

Immunolipid magnetic bead-based circulating tumor cell sorting: a novel approach for pathological staging of colorectal cancer.

Deng Q, Li W, Huang Y, Wang H, Zhou X, Guan Z Front Oncol. 2025; 14:1531972.

PMID: 39927117 PMC: 11803635. DOI: 10.3389/fonc.2024.1531972.

C19MC drives nucleolar invasion of mitochondria and meiotic nuclear division in human cancers.

Jinesh G, Smallin M, Mtchedlidze N, Napoli M, Lockhart J, Flores E iScience. 2024; 27(11):111132.

PMID: 39563898 PMC: 11575172. DOI: 10.1016/j.isci.2024.111132.

Let's make it personal: CRISPR tools in manipulating cell death pathways for cancer treatment.

Bayat M, Nahand J Cell Biol Toxicol. 2024; 40(1):61.

PMID: 39075259 PMC: 11286699. DOI: 10.1007/s10565-024-09907-z.

Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling.

Rahman M, Nguyen T, Lee G, Kim B, Park M, Lee C Int J Mol Sci. 2024; 25(3).

PMID: 38338768 PMC: 10855792. DOI: 10.3390/ijms25031489.

Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces.

Safa A Cancer Drug Resist. 2023; 5(4):850-872.

PMID: 36627897 PMC: 9771762. DOI: 10.20517/cdr.2022.20.

References

Hardwick J, Soane L . Multiple functions of BCL-2 family proteins. Cold Spring Harb Perspect Biol. 2013; 5(2). PMC: 3552500. DOI: 10.1101/cshperspect.a008722. View

Rosen K, Rak J, Jin J, Kerbel R, Newman M, Filmus J . Downregulation of the pro-apoptotic protein Bak is required for the ras-induced transformation of intestinal epithelial cells. Curr Biol. 1998; 8(24):1331-4. DOI: 10.1016/s0960-9822(07)00564-7. View

Hah J, Zhao M, Pickering C, Frederick M, Andrews G, Jasser S . HRAS mutations and resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in head and neck squamous cell carcinoma cells. Head Neck. 2013; 36(11):1547-54. PMC: 4010580. DOI: 10.1002/hed.23499. View

Shih S, Mullen A, Abrams K, Mukhopadhyay D, Claffey K . Role of protein kinase C isoforms in phorbol ester-induced vascular endothelial growth factor expression in human glioblastoma cells. J Biol Chem. 1999; 274(22):15407-14. DOI: 10.1074/jbc.274.22.15407. View

Gupta S, Kass G, Szegezdi E, Joseph B . The mitochondrial death pathway: a promising therapeutic target in diseases. J Cell Mol Med. 2009; 13(6):1004-33. PMC: 4496101. DOI: 10.1111/j.1582-4934.2009.00697.x. View

Jinesh G, Choi W, Shah J, Lee E, Willis D, Kamat A . Blebbishields, the emergency program for cancer stem cells: sphere formation and tumorigenesis after apoptosis. Cell Death Differ. 2012; 20(3):382-95. PMC: 3569985. DOI: 10.1038/cdd.2012.140. View

Roe J, Kim H, Lee S, Kim S, Cho E, Youn H . p53 stabilization and transactivation by a von Hippel-Lindau protein. Mol Cell. 2006; 22(3):395-405. DOI: 10.1016/j.molcel.2006.04.006. View

Kim E, Kim A, Kim S, Chang Y . AZD6244 inhibits cisplatin-induced ERK1/2 activation and potentiates cisplatin-associated cytotoxicity in K-ras G12D preclinical models. Cancer Lett. 2014; 358(1):85-91. DOI: 10.1016/j.canlet.2014.12.041. View

Sato M, Kawana K, Adachi K, Fujimoto A, Yoshida M, Nakamura H . Spheroid cancer stem cells display reprogrammed metabolism and obtain energy by actively running the tricarboxylic acid (TCA) cycle. Oncotarget. 2016; 7(22):33297-305. PMC: 5078095. DOI: 10.18632/oncotarget.8947. View

10.

Jinesh G, Napoli M, Ackerman H, Raulji P, Montey N, Flores E . Regulation of MYO18B mRNA by a network of C19MC miRNA-520G, IFN-γ, CEBPB, p53 and bFGF in hepatocellular carcinoma. Sci Rep. 2020; 10(1):12371. PMC: 7378193. DOI: 10.1038/s41598-020-69179-5. View

11.

Jinesh G, Mokkapati S, Zhu K, Morales E . Pim kinase isoforms: devils defending cancer cells from therapeutic and immune attacks. Apoptosis. 2016; 21(11):1203-1213. DOI: 10.1007/s10495-016-1289-3. View

12.

Jinesh G, Kamat A . Blebbishields and mitotic cells exhibit robust macropinocytosis. Biofactors. 2016; 43(2):181-186. DOI: 10.1002/biof.1335. View

13.

Lane D . Cell immortalization and transformation by the p53 gene. Nature. 1984; 312(5995):596-7. DOI: 10.1038/312596a0. View

14.

Mylroie H, Dumont O, Bauer A, Thornton C, Mackey J, Calay D . PKCε-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis. Cardiovasc Res. 2015; 106(3):509-19. PMC: 4431664. DOI: 10.1093/cvr/cvv131. View

15.

Nomura Y, Tashiro H, Hisamatsu K . In vitro clonogenic growth and metastatic potential of human operable breast cancer. Cancer Res. 1989; 49(19):5288-93. View

16.

Gottardi C, Wong E, Gumbiner B . E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner. J Cell Biol. 2001; 153(5):1049-60. PMC: 2174337. DOI: 10.1083/jcb.153.5.1049. View

17.

Okada F, Rak J, Croix B, Lieubeau B, Kaya M, Roncari L . Impact of oncogenes in tumor angiogenesis: mutant K-ras up-regulation of vascular endothelial growth factor/vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells. Proc Natl Acad Sci U S A. 1998; 95(7):3609-14. PMC: 19883. DOI: 10.1073/pnas.95.7.3609. View

18.

Khanal P, Choi H, Namgoong G, Ahn S, Yoon J, Sohn H . 5'-Nitro-indirubinoxime inhibits epidermal growth factor- and phorbol ester-induced AP-1 activity and cell transformation through inhibition of phosphorylation of Pin1. Mol Carcinog. 2011; 50(12):961-71. DOI: 10.1002/mc.20761. View

19.

Hoogwater F, Nijkamp M, Smakman N, Steller E, Emmink B, Westendorp B . Oncogenic K-Ras turns death receptors into metastasis-promoting receptors in human and mouse colorectal cancer cells. Gastroenterology. 2010; 138(7):2357-67. DOI: 10.1053/j.gastro.2010.02.046. View

20.

Tchernitsa O, Sers C, Zuber J, Hinzmann B, Grips M, Schramme A . Transcriptional basis of KRAS oncogene-mediated cellular transformation in ovarian epithelial cells. Oncogene. 2004; 23(26):4536-55. DOI: 10.1038/sj.onc.1207585. View