Cell death is an important mechanism in the pathogenesis of many diseases as well as
homeostasis in adult tissues. Dr. Pothana Saikumar's research is aimed at elucidating the biochemical and
molecular mechanisms of cell death that occurs in the context of hypoxia as well as
Mitochondrial outer membrane permeabilization, associated with
most apoptotic stimuli, results in the release of apoptogenic proteins like Cytochrome c,
Smac/DIABLO, and HtrA2/Omi from mitochondria and is regulated by both pro- and
anti- apoptotic members of the Bcl-2 family of proteins. They have previously shown that
hypoxia induces the translocation of Bax, a death promoting protein, from cytosol to
mitochondria, followed by its oligomerization along with Bak protein in the membrane
and release of cytochrome c from mitochondria to the cytosol.
Recently, a model
involving mitochondrial fragmentation has been suggested as a complementary
mechanism for mitochondrial outer membrane permeabilization.
However, their studies
identified 15d-PGJ2, a product of inflammatory COX-2 during reoxygenation, inducing
cell death with mitochondrial fusion preceding the death. They are currently studying the
mechanisms involved in the dynamic alterations of mitochondrial shape associated with
Many cancers are resistant to classical drug/radiation therapies, which induce
apoptosis. In this regard, they have identified compounds that could induce nonapoptotic
cell death termed as cytoplasmic vacuolation death or paraptosis in apoptosis
resistant cancer cells. They reported that upregulation and processing of autophagy
marker LC3 is an important event in non-autophagic cytoplasmic vacuolation death. They are further exploring the signaling mechanisms of this novel death pathway as well as of
its utility in treating therapy resistant cancers.
Molecular basis by which a tumor suppressive TGF-β signaling promotes tumor
progression in advanced cancers is not known. They recently identified a TGF-β
responsive gene TMEPAI (transmembrane prostate androgen-induced protein), whose
expression is increased in several breast tumors. TMEPAI blocks TGF-β signaling
through possible sequestration of R-Smads thus converting TGF-β from a tumor
suppressor to a tumor promoter. Their current research explores the mechanisms by
which TMEPAI alters TGF-β signaling and its role in tumorigenicity.
Singha PK, Pandeswara S, Venkatachalam MA, Saikumar P. Manumycin A inhibits triple-negative breast cancer growth through LC3-mediated cytoplasmic vacuolation death. Cell Death Dis. 2013 Jan 17;4:e457.
Nair HB, Perla RP, Kirma NB, Krishnegowda NK, Ganapathy M, Rajhans R, Nair SS, Saikumar P, Vadlamudi RK, Tekmal RR. Estrogen
receptor-beta mediates the protective effects of aromatase induction in
the MMTV-Her-2/neu x aromatase double transgenic mice. Horm Cancer. 2012 Apr;3(1-2):26-36.
Lan R, Geng H, Polichnowski AJ, Singha PK, Saikumar P, McEwen DG,
Griffin KA, Koesters R, Weinberg JM, Bidani AK, Kriz W, Venkatachalam
MA. PTEN loss defines a TGF-β-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis. Am J Physiol Renal Physiol. 2012 May 1;302(9):F1210-23.
Geng H, Lan R, Singha PK, Gilchrist A, Weinreb PH, Violette SM, Weinberg JM, Saikumar P, Venkatachalam MA. Lysophosphatidic
acid increases proximal tubule cell secretion of profibrotic cytokines
PDGF-B and CTGF through LPA2- and Gαq-mediated Rho and αvβ6
integrin-dependent activation of TGF-β. Am J Pathol. 2012 Oct;181(4):1236-49.
Lan R, Geng H, Hwang Y, Mishra P, Skloss WL, Sprague EA, Saikumar P, Venkatachalam M. A novel wounding device suitable for quantitative biochemical analysis of wound healing and regeneration of cultured epithelium. Wound Repair Regen. 2010 Mar-Apr;18(2):159-67.