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Activation of p53/p21/PUMA alliance and disruption of PI‐3/Akt in multimodal targeting of apoptotic signaling cascades in cervical cancer cells by a pentacyclic triterpenediol from Boswellia serrata
Author(s) -
Bhushan Shashi,
Malik Fayaz,
Kumar Ajay,
Isher Harpreet Kaur,
Kaur Indu Pal,
Taneja Subhash Chandra,
Singh Jaswant
Publication year - 2009
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20559
Subject(s) - biology , xiap , protein kinase b , apoptosis , hela , pi3k/akt/mtor pathway , signal transduction , microbiology and biotechnology , survivin , caspase , programmed cell death , cancer cell , cancer research , cytochrome c , inhibitor of apoptosis , puma , mitochondrion , cancer , cell , biochemistry , genetics
Cervical carcinoma is a growing menace to women health worldwide. This study reports the apoptotic cell death in human cervical cancer HeLa and SiHa cells by a pentacyclic triterpenediol (TPD) from Boswellia serrata by a mechanism different from reported in HL‐60 cells. It caused oxidative stress by early generation of nitric oxide and reactive oxygen species that robustly up regulated time‐dependent expression of p53/p21/PUMA while conversely abrogating phosphatidylinositol‐3‐kinase (PI3K)/Akt pathways in parallel. TPD also decreased the expression of PI3K/pAkt, ERK1/2, NF‐κB/Akt signaling cascades which coordinately contribute to cancer cell survival through these distinct pathways. The tumor suppressor p53 pathway predominantly activated by TPD further up‐regulated PUMA, which concomitantly decreased the Bcl‐2 level, caused mitochondrial membrane potential loss with attendant translocation of Bax and drp1 to mitochondria and release of pro‐apoptotic factors such as cytochrome c and Smac/Diablo to cytosol leading to caspases‐3 and ‐9 activation. In addition both the phospho‐p53 and p21 were found to accumulate heavily in the nuclear fraction with attendant decrease in topoisomarase II and survivin levels. On the contrary, TPD did not affect the extrinsic signaling transduction pathway effectively through apical death receptors. Interestingly, N ‐acetyl cysteine, ascorbate and s‐methylisothiourea (sMIT) rescued cells significantly from TPD induced DNA damage and caspases activation. TPD may thus find usefulness in managing and treating cervical cancer. © 2009 Wiley‐Liss, Inc.