The phosphatase and tensin homolog (PTEN) and its downstream target PI3K/Akt/mTOR axis, play a

significant role in regulating the proliferation of cancer cells and governing their response to

therapeutic drugs. Briefly, PI3K/Akt/mTOR activation leads to increased cancer progression, and as a

tumor-suppressor factor, PTEN disrupts the aforementioned axis to inhibit cancer growth, and promote

drug sensitivity [93–99]. It seems that TGF-β1 and TGF-β3 are both able to affect PTEN in PCa cells.

However, TGF-β1 and TGF-β3 do not affect PTEN at the mRNA level, but increase the activity of

PTEN to suppress PCa growth. Furthermore, the TGF-β isoforms suppress Akt phosphorylation via

up-regulating PTEN expression [100]. In vivo studies on tumorbearing mice also revealed that the

silencing of stromal TGFβRII led to Wnt3a up-regulation and enhanced PCa proliferation [101]. The

speckle-type pox virus and zinc finger protein (SPOP) is an E3 ubiquitin ligase called Cullin3 that

undergoes mutations in various cancers, particularly PCa. Some tumor-promoting factors affect the

stability of SPOP to mediate PCa progression. It has been reported that Snail can increase the

progression of PCa cells via causing SPOP degradation via ubiquitination [102]. Upon SPOP

degradation, a number of downstream targets, such as c-Myc, AR, and Arv7 are up-regulated leading

to CRPC progression [103]. Furthermore, SPOP mutations can increase the intratumoral androgen

synthesis and promote PCa progression [104]. TGF-β signaling can also affect SPOP to stimulate PCa

progression. Smad3 is a major component of the TGF-β signaling pathway with binding sites on the

SPOP promoter, known as SMAD-binding elements (SBEs). Smad3 can reduce the expression level of

SPOP to enhance PCa stemness. Besides, SPOP down-regulation by TGF-β was correlated with the

poor prognosis of PCa patients [105]. However, another study demonstrated a tumor-suppressor role of

TGF-β in PCa, via enhancing the expression of miRNA-3691–3p, with a subsequent decrease in

expression levels of E2F3 and PRDM1 [106]. In fact, the exact role of TGF-β in PCa is still uncertain,

and each study suggests a different pathway and role for this cytokine. Further experiments will likely

shed more light on this subject.

TGF-β1 increases the secretion of matrix metalloproteinase 9 (MMP-9),